CN103221405A - Substituted pyridine compound - Google Patents

Abstract

Disclosed is a substituted pyridine compound that has excellent CETP inhibiting activity and is useful as a pharmaceutical, or a pharmacologically acceptable salt thereof. Specifically disclosed is a compound, etc., that fulfills a general formula (I) (wherein, R1: H, substitutable alkyl, OH, optionally substituted alkoxy, alkylsulfonyl, optionally substituted amino, carboxy, optionally substituted carbonyl, CN, halogen, optionally substituted phenyl, optionally substituted aromatic heterocyclyl, optionally substituted saturated heterocyclyl, optionally substituted saturated heterocyclyloxy, optionally substituted saturated heterocyclylcarbonyl, etc.)

Description

Substituted pyridine compounds

technical field

The present invention relates to a substituted pyridine compound or a pharmaceutically acceptable salt thereof, which has excellent CETP inhibitory activity and is used as a medicine (especially a medicine for treating or preventing dyslipidemia, low HDL cholesterolemia, arteriosclerosis or coronary heart disease) new.

Background technique

The results of many epidemiological investigations have shown that serum lipoprotein concentrations are involved in diseases such as dyslipidemia and arteriosclerosis (eg, Badimon, J. Clin. Invest., 1990, Vol. 85, pp. 1234-1241). An increase in the concentration of low-density lipoprotein (hereinafter referred to as LDL) cholesterol in the blood and a decrease in the concentration of high-density lipoprotein (hereinafter referred to as HDL) cholesterol in the blood are both risk factors for coronary artery disease.

Cholesterol in peripheral tissues is extracted by HDL and esterified in HDL to become cholesteryl ester (hereinafter referred to as CE). Cholesteryl ester transfer protein (hereinafter referred to as CETP) transfers CE in HDL to LDL. Thus, inhibition of CETP action increases CE concentrations in HDL and decreases CE concentrations in LDL. As described above, drugs that inhibit CETP activity are considered as drugs for treating or preventing diseases such as dyslipidemia and arteriosclerosis (for example, N. Engl. J. Med., 2004, vol. 350, pp. 1505-1515).

Certain pyridine compounds are known to have CETP inhibitory activity (for example, see Patent References 1-8). In addition, certain pyrimidinylpiperidine compounds having CETP inhibitory activity are also known (for example, see Patent References 9-13).

Prior Art References

Patent References

Patent Reference 1: Japanese Patent Application Laid-Open (JP-A) No. Hei 10-067746 (Corresponding U.S. Patents: U.S. Patent No. 6,069,148 and U.S. Patent No. 6,207,671)

Patent Reference 2: Japanese Patent Application National Publication No. 2001-516757 (Corresponding US Patent: US Patent No. 6,387,929)

Patent Reference 3: Japanese Patent Application National Publication No. 2001-517655 (Corresponding U.S. Patents: U.S. Patent No. 6,291,477, U.S. Patent No. 6,562,976, and U.S. Patent No. 6,897,317)

Patent Reference 4: Japanese Patent Application National Publication No. 2005-508341 (Corresponding U.S. Patent Application: U.S. Application Publication No. 2005/0043341)

Patent Reference 5: Japanese Patent Application Laid-Open (JP-A) No. Hei 10-167967 (Corresponding US Patent: US Patent No. 5,932,587)

Patent Reference 6: Japanese Patent Application National Publication No. 2008-524145 (Corresponding U.S. Application: U.S. Application Publication No. 2008/0255068)

Patent Reference 7: Japanese Patent Application National Publication No. 2008-524137 (Corresponding U.S. Application: U.S. Application Publication No. 2008/0194609)

Patent Reference 8: International Publication No. WO2009/109549

Patent Reference 9: Japanese Patent Application National Publication No. 2009-516649 (Corresponding U.S. Application: U.S. Application Publication No. 2009/0264405)

Patent Reference 10: International Publication No. WO2008/156715

Patent Reference 11: Japanese Patent Application National Publication No. 2009-524579 (Corresponding U.S. Application: U.S. Application Publication No. 2009/0023729)

Patent Reference 12: International Publication No. WO2008/009435 (Corresponding US Application: US Application Publication No. 2009/0286790)

Patent Reference 13: International Publication No. WO2009/071509

invention disclosure

purpose of invention

The inventors have studied novel substituted pyridine compounds with the aim of developing excellent CETP inhibitors and found that they have excellent CETP inhibitory activity and are useful as medicines (particularly, for the treatment or prevention of dyslipidemia, low HDL cholesterolemia, arterial A substituted pyridine compound having a specific structure or a pharmaceutically acceptable salt thereof. Based on the above findings, the present invention has been accomplished.

way to achieve the goal

The present invention provides novel substituted pyridine compounds or pharmaceutically acceptable salts thereof with excellent CETP inhibitory activity;

A pharmaceutical composition comprising a substituted pyridine compound or a pharmaceutically acceptable salt thereof as an active ingredient, and for use in the treatment or prevention of preferably dyslipidemia, hypercholesterolemia, hypo-HDL cholesterolemia, hyper-HDL cholesterolemia, Hypertriglyceridemia, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease (including heart failure, myocardial infarction, angina pectoris, myocardial ischemia, cardiovascular disorders and restenosis involving angioplasty), cerebrovascular disease ( Including stroke and cerebral infarction), peripheral vascular disease (including diabetic vascular complications) or obesity, more preferably dyslipidemia, low HDL cholesterol, high HDL cholesterol, arteriosclerosis, arteriosclerotic heart disease or coronary heart disease , further preferably dyslipidemia, hypo-HDL cholesterol, arteriosclerosis or coronary heart disease, and even more preferably a pharmaceutical composition for hypo-HDL cholesterol or arteriosclerosis;

Use of a substituted pyridine compound or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating or preventing (preferably treating) a disease (preferably the above-mentioned diseases);

A method for treating or preventing (preferably treating) a disease (preferably the above-mentioned disease), which comprises administering a pharmacologically effective amount of a substituted pyridine compound or a pharmaceutically acceptable salt thereof to a warm-blooded animal (preferably human); and

Process for preparing substituted pyridine compounds or pharmaceutically acceptable salts or intermediates thereof.

In one aspect, the invention provides the following.

(1A) A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

Wherein R ¹ represents a hydrogen atom, C ₁ -C ₆ alkyl, hydroxyl (C ₁ -C ₆ alkyl) group, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group , hydroxyl (C ₁ -C ₆ alkoxy) - (C ₁ -C ₆ alkyl) group, (C ₁ -C ₆ alkyl) amino - (C ₁ -C ₆ alkyl) group, hydroxyl ( C ₁ -C ₆ alkyl)amino-(C ₁ -C ₆ alkyl) group, [N-(C ₁ -C ₆ alkyl)-N-hydroxyl(C ₁ -C ₆ alkyl)amino]- (C ₁ -C ₆ alkyl) group, (C ₁ -C ₆ alkyl)sulfonylamino-(C ₁ -C ₆ alkyl) group, [N-(C ₁ -C ₆ alkyl)- N-(C ₁ -C ₆ alkyl)sulfonylamino]-(C ₁ -C ₆ alkyl) group, carboxyl (C ₁ -C ₆ alkyl) group, halogenated (C ₁ -C ₆ alkane group) group, (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl) group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₃ -C ₈ Cycloalkyl, C ₃ -C ₈ cycloalkenyl, hydroxyl, C ₁ -C ₆ alkoxy, hydroxyl (C ₁ -C ₆ alkoxy) group, (C ₁ -C ₆ alkoxy)-( C ₁ -C ₆ alkoxy) group, (C ₁ -C ₆ alkyl)sulfonyl-(C ₁ -C ₆ alkoxy) group, carboxyl (C ₁ -C ₆ alkoxy) group , halogenated (C ₁ -C ₆ alkoxy) group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ alkylsulfinyl group, C ₁ -C ₆ alkylsulfonyl group, amino group, C ₁ -C ₆ alkylamino, di(C ₁ -C ₆ alkyl)amino, hydroxy(C ₁ -C ₆ alkyl)amino, N-(C ₁ -C ₆ alkyl)-N-hydroxyl (C ₁ -C ₆ alkyl)amino, formylamino, (C ₁ -C ₆ alkyl)carbonylamino, carboxyl, (C ₁ -C ₆ alkoxy)carbonyl, carbamoyl, (C ₁ -C ₆ alkyl Amino)carbonyl, di(C ₁ -C ₆ alkyl)aminocarbonyl, cyano, halo, phenyl, wherein the substituents represent substituted benzenes independently selected from 1-4 groups of substituent group α group, 5-membered or 6-membered aromatic heterocyclic group, wherein the substituent represents a substituted 5-membered or 6-membered aromatic heterocyclic group independently selected from 1-4 groups of substituent group α, 5-membered Or a 6-membered saturated heterocyclic group, wherein the substituent represents a substituted 5-membered or 6-membered saturated heterocyclic group, a 5-membered or 6-membered saturated heterocyclic group independently selected from 1-4 groups of substituent group α -(C ₁ -C ₆ alkyl) group, wherein the substituent represents a substituted 5-membered or 6-membered saturated heterocyclic ring independently selected from 1-4 groups of substituent group α-(C ₁ -C ₆ Alkyl) group, 5-membered or 6-membered saturated heterocyclyloxy group, wherein the substituent represents independently selected from substituent group α 1-4 substituted 5-membered or 6-membered saturated heterocyclyloxy groups, 5-membered or 6-membered saturated heterocyclylcarbonyl groups or wherein the substituents represent 1-4 groups independently selected from substituent group α A substituted 5- or 6-membered saturated heterocyclylcarbonyl group, and

Substituent α represents C ₁ -C ₆ alkyl, hydroxyl (C ₁ -C ₆ alkyl) group, halogenated (C ₁ -C ₆ alkyl) group, (C ₃ -C ₈ cycloalkyl)- (C ₁ -C ₆ alkyl) group, C ₃ -C ₈ cycloalkyl, hydroxyl, C ₁ -C ₆ alkoxy, halogenated (C ₁ -C ₆ alkoxy) group, C ₁ - C ₆ alkylamino, di(C ₁ -C ₆ alkyl) amino, carboxyl, (C ₁ -C ₆ alkoxy) carbonyl, carbamoyl, (C ₁ -C ₆ alkylamino) carbonyl, di( C ₁ -C ₆ alkyl)aminocarbonyl, cyano, halo and oxo.

(2A) The compound according to (1A) represented by general formula (I-1) or a pharmaceutically acceptable salt thereof:

(3A) The compound according to (2A) or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom, C ₁ -C ₆ alkyl, hydroxyl (C ₁ -C ₆ alkyl) group, (C ₁ - C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, (C ₁ -C ₆ alkyl) amino-(C ₁ -C ₆ alkyl) group, [N-(C ₁ -C ₆ alkyl)-N-hydroxyl(C ₁ -C ₆ alkyl)amino]-(C ₁ -C ₆ alkyl) group, [N-(C ₁ -C ₆ alkyl)-N-(C ₁ -C ₆ alkyl)sulfonylamino]-(C ₁ -C ₆ alkyl) group, carboxyl (C ₁ -C ₆ alkyl) group, halogenated (C ₁ -C ₆ alkyl) group, C _{2 -C 6} alkenyl, C ₃ -C 8 cycloalkyl, C ₃ -C ₈ cycloalkenyl, hydroxyl, C ₁ -C ₆ alkoxy, hydroxy(C ₁ -C ₆ alkoxy) group group, (C ₁ -C ₆ alkyl)sulfonyl-(C ₁ -C ₆ alkoxy) group, carboxyl (C ₁ -C ₆ alkoxy) group, halogenated (C ₁ -C ₆ alkoxy) group Oxy) group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ alkylsulfonyl group, N-(C ₁ -C ₆ alkyl)-N-hydroxyl (C ₁ -C ₆ alkyl) Amino, (C ₁ -C ₆ alkylamino)carbonyl, di(C ₁ -C ₆ alkyl)aminocarbonyl, cyano or halo.

(4A) The compound according to (2A) or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom, C ₁ -C ₄ alkyl, hydroxyl (C ₁ -C ₄ alkyl) group, (C ₁ - C ₄ alkoxy)-(C ₁ -C ₄ alkyl) group, halogenated (C ₁ -C ₄ alkyl) group, C ₁ -C ₄ alkoxy, hydroxy (C ₁ -C ₆ alk oxy) group or (C ₁ -C ₄ alkyl)sulfonyl-(C ₁ -C ₄ alkoxy) group.

(5A) The compound according to (2A) or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁ -C ₄ alkyl, halogenated (C ₁ -C ₄ alkyl) group, C ₁ -C ₄ alkane Oxy or hydroxy(C ₁ -C ₆ alkoxy) group.

(6A) The compound according to (2A), or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁ -C ₄ alkyl.

(7A) The compound according to (2A), or a pharmaceutically acceptable salt thereof, wherein R ¹ is a halo(C ₁ -C ₄ alkyl) group.

(8A) The compound according to (2A), or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁ -C ₄ alkoxy.

(9A) The compound according to (2A), or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydroxy(C ₁ -C ₆ alkoxy) group.

(10A) The compound according to (2A), or a pharmaceutically acceptable salt thereof, wherein R ¹ is a (C ₁ -C ₄ alkyl)sulfonyl-(C ₁ -C ₄ alkoxy) group.

(11A) The compound according to (2A), or a pharmaceutically acceptable salt thereof, wherein

^R is wherein the substituent represents a substituted phenyl group independently selected from 1-4 groups of substituent group α1, wherein the substituent represents substitution of 1-4 groups independently selected from substituent group α1 5-membered or 6-membered aromatic heterocyclic group, 5-membered or 6-membered saturated heterocyclic group, wherein the substituent represents a substituted 5-membered or 6-membered group independently selected from 1-4 groups of substituent group α1 A saturated heterocyclic group, wherein the substituent represents a substituted 5-membered or 6-membered saturated heterocyclic group oxy group or a 5-membered or 6-membered saturated heterocyclic groupcarbonyl group independently selected from 1-4 groups of the substituent group α1 ,and

The substituent group α1 represents a C ₁ -C ₆ alkyl group, a hydroxyl group, a carboxyl group and an oxo group.

(12A) The compound according to (2A), or a pharmaceutically acceptable salt thereof, wherein

^R is a 5-membered or 6-membered nitrogen-containing saturated heterocyclic group, wherein the substituent represents a substituted 5-membered or 6-membered nitrogen-containing saturated heterocyclic group independently selected from 1-4 groups of substituent group α2 , wherein the substituent represents a substituted 5-membered or 6-membered nitrogen-containing saturated heterocyclic group oxy group or a 5-membered or 6-membered nitrogen-containing saturated heterocyclic groupcarbonyl group independently selected from 1-4 groups of substituent group α2, and

Substituent group α2 represents a C ₁ -C ₄ alkyl group and a hydroxyl group.

(13A) The compound according to (2A), or a pharmaceutically acceptable salt thereof, wherein

^R is substituted pyrrolidinyl, substituted piperazinyl, substituted pyrrolidinyloxy or substituted piperidinyloxy, wherein pyrrolidinyl, piperazinyl, pyrrolidinyloxy and piperidinyloxy The substituent of the group represents 1-2 groups independently selected from substituent group α3 or morpholinocarbonyl, and

Substituent group α3 represents a methyl group and a hydroxyl group.

(14A) The compound according to (2A) or a pharmaceutically acceptable salt thereof, wherein R ¹ is a substituted phenyl group, wherein the substituents represent 1-2 groups independently selected from substituent group α1.

(15A) The compound according to (2A) or a pharmaceutically acceptable salt thereof, which is selected from

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl- 2-{1-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol ,

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5- (2-hydroxyethoxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol,

(5S)-2-{1-[5-(4-carboxybutoxy)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluorocyclohexyl)-3-{ (S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol,

(5S)-2-{1-[5-(4-carboxybutyl)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluorocyclohexyl)-3-{( S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol,

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl- 2-{1-[5-(methylcarbamoyl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol,

(5S)-4-(4,4-difluorocyclohexyl)-2-{1-[5-(dimethylcarbamoyl)pyrimidin-2-yl]piperidin-4-yl}-3-{ (S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol,

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl- 2-{1-[5-(morpholin-4-ylcarbonyl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol,

(5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-(5- {[(2-Hydroxyethyl)(methyl)amino]methyl}pyrimidin-2-yl)piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydro Quinolin-5-ol,

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5- {[(2S)-2-Hydroxypropyl]oxy}pyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline- 5-alcohol,

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl- 2-(1-{5-[(1-methylpiperidin-4-yl)oxy]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinoline -5-ol,

(5S)-4-(4,4-difluorocyclohexyl)-2-[1-(5-{[(2S)-2,3-dihydroxypropyl]oxy}pyrimidin-2-yl)piper Pyridin-4-yl]-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydro Quinolin-5-ol,

(5S)-4-(4,4-difluorocyclohexyl)-2-[1-(5-{[(2R)-2,3-dihydroxypropyl]oxy}pyrimidin-2-yl)piper Pyridin-4-yl]-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydro Quinolin-5-ol,

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl- 2-[1-(5-{[(3R)-1-methylpyrrolidin-3-yl]oxy}pyrimidin-2-yl)piperidin-4-yl]-5,6,7,8- Tetrahydroquinolin-5-ol,

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5- {[(2R)-2-Hydroxypropyl]oxy}pyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline- 5-alcohol,

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5- (3-Hydroxy-3-methylbutoxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5- alcohol,

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5- (2-Hydroxy-2-methylpropoxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5- alcohol,

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl- 2-(1-{5-[3-(methylsulfonyl)propoxy]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinolin-5-ol ,

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5- (3-hydroxypropoxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol,

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl- 2-{1-[5-(3,3,3-trifluoropropoxy)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinoline-5- alcohol,

(5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5- [3-Hydroxy-2-(hydroxymethyl)propoxy]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinoline -5-ol,

(5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5- [3-Hydroxy-2-(hydroxymethyl)-2-methylpropoxy]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8 -tetrahydroquinolin-5-ol,

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl- 2-[1-(5-{[Methyl(methylsulfonyl)amino]methyl}pyrimidin-2-yl)piperidin-4-yl]-5,6,7,8-tetrahydroquinoline-5 -alcohol,

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl- 2-[1-(5-{[Methyl(prop-2-ylsulfonyl)amino]methyl}pyrimidin-2-yl)piperidin-4-yl]-5,6,7,8-tetrahydro Quinolin-5-ol,

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl- 2-[1-(5-methylthiopyrimidin-2-yl)piperidin-4-yl]-5,6,7,8-tetrahydroquinolin-5-ol,

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl- 2-{1-[5-(methylsulfonyl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol,

(5S)-2-{1-[5-(3-carboxyphenyl)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluorocyclohexyl)-3-{( S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol,

(5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5- [(2-Hydroxyethyl)(methyl)amino]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5 -alcohol, and

(5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5- [(3S)-3-Hydroxypyrrolidin-1-yl]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinoline- 5-ol.

(16A) A pharmaceutical composition containing the compound according to any one of (1A) to (15A) or a pharmaceutically acceptable salt thereof as an active ingredient.

(17A) For the treatment or prevention of dyslipidemia, hypercholesterolemia, low HDL cholesterolemia, high HDL cholesterolemia, hypertriglyceridemia, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, cerebrovascular disease , a pharmaceutical composition according to (16A) for peripheral vascular disease or obesity.

(18A) The pharmaceutical composition according to (16A) for treating or preventing dyslipidemia, low HDL cholesterolemia, arteriosclerosis or coronary heart disease.

(19A) The pharmaceutical composition according to (16A) for treating or preventing hypo-HDL cholesterolemia.

(20A) The pharmaceutical composition according to (16A) for treating or preventing arteriosclerosis.

(21A) The pharmaceutical composition according to (16A) for treating or preventing a disease caused by a decrease in blood HDL cholesterol concentration.

(22A) The pharmaceutical composition according to (16) for treating or preventing a disease caused by an increase in the concentration of LDL cholesterol in blood.

(23A) A CETP-inhibiting drug comprising, as an active ingredient, the compound according to any one of (1A) to (15A) or a pharmaceutically acceptable salt thereof.

(24A) A drug for increasing HDL cholesterol concentration, comprising the compound according to any one of (1A) to (15A) or a pharmaceutically acceptable salt thereof as an active ingredient.

(25A) A drug for lowering LDL cholesterol concentration, which contains the compound according to any one of (1A) to (15A) or a pharmaceutically acceptable salt thereof as an active ingredient.

(26A) Use of the compound according to any one of (1A)-(15A) or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition.

(27A) according to (26A) in the preparation treatment or prevention of dyslipidemia, hypercholesterolemia, hypo-HDL cholesterolemia, hyper-HDL cholesterolemia, hypertriglyceridemia, arteriosclerosis, arteriosclerotic heart disease, coronary The use of the pharmaceutical composition for heart disease, cerebrovascular disease, peripheral vascular disease or obesity.

(28A) Use according to (26A) for the preparation of a pharmaceutical composition for treating or preventing dyslipidemia, low HDL cholesterolemia, arteriosclerosis or coronary heart disease.

(29A) Use according to (26A) for the manufacture of a pharmaceutical composition for treating or preventing hypo-HDL cholesterolemia.

(30A) The use according to (26A) for the preparation of a pharmaceutical composition for treating or preventing arteriosclerosis.

(31A) The compound according to any one of (1A) to (15A) or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing a disease.

(32A) The compound according to (31A) or a pharmaceutically acceptable salt thereof, wherein the disease is dyslipidemia, hypercholesterolemia, hypo-HDL cholesterolemia, hyper-HDL cholesterolemia, hypertriglyceridemia, arterial sclerosis, arteriosclerotic heart disease, coronary heart disease, cerebrovascular disease, peripheral vascular disease, or obesity.

(33A) The compound according to (31A) or a pharmaceutically acceptable salt thereof, wherein the disease is dyslipidemia, low HDL cholesterolemia, arteriosclerosis or coronary heart disease.

(34A) The compound according to (31A) or a pharmaceutically acceptable salt thereof, wherein the disease is low HDL cholesterolemia.

(35A) The compound according to (31A) or a pharmaceutically acceptable salt thereof, wherein the disease is arteriosclerosis.

(36A) A method for treating or preventing a disease, which comprises administering a pharmacologically effective amount of the compound according to any one of (1A) to (15A) or a pharmaceutically acceptable salt thereof to a warm-blooded animal.

(37A) The method according to (36A), wherein the disease is dyslipidemia, hypercholesterolemia, hypo-HDL cholesterolemia, hyper-HDL cholesterolemia, hypertriglyceridemia, arteriosclerosis, arteriosclerotic heart disease, Coronary heart disease, cerebrovascular disease, peripheral vascular disease, or obesity.

(38A) The method according to (36A), wherein the disease is dyslipidemia, low HDL cholesterolemia, arteriosclerosis or coronary heart disease.

(39A) The method according to (36A), wherein the disease is low HDL cholesterolemia.

(40A) The method according to (36A), wherein the disease is arteriosclerosis.

(41A) The method according to any one of (36A)-(40A), wherein the warm-blooded animal is human.

Additionally, in one aspect, the present invention provides the following:

(1) A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

Wherein R ¹ represents a hydrogen atom, C ₁ -C ₆ alkyl, hydroxyl (C ₁ -C ₆ alkyl) group, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group , hydroxyl (C ₁ -C ₆ alkoxy) - (C ₁ -C ₆ alkyl) group, (C ₁ -C ₆ alkyl) amino - (C ₁ -C ₆ alkyl) group, hydroxyl ( C ₁ -C ₆ alkyl)amino-(C ₁ -C ₆ alkyl) group, [N-(C ₁ -C ₆ alkyl)-N-hydroxyl(C ₁ -C ₆ alkyl)amino]- (C ₁ -C ₆ alkyl) group, (C ₁ -C ₆ alkyl)sulfonylamino-(C ₁ -C ₆ alkyl) group, [N-(C ₁ -C ₆ alkyl)- N-(C ₁ -C ₆ alkyl)sulfonylamino]-(C ₁ -C ₆ alkyl) group, carboxyl (C ₁ -C ₆ alkyl) group, halogenated (C ₁ -C ₆ alkane group) group, (C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl) group, C ₂ -C ₆ alkenyl group, C ₂ -C ₆ alkynyl group, C ₃ -C ₈ Cycloalkyl, C ₃ -C ₈ cycloalkenyl, hydroxyl, C ₁ -C ₆ alkoxy, hydroxyl (C ₁ -C ₆ alkoxy) group, (C ₁ -C ₆ alkoxy)-( C ₁ -C ₆ alkoxy) group, (C ₁ -C ₆ alkyl)sulfonyl-(C ₁ -C ₆ alkoxy) group, carboxyl (C ₁ -C ₆ alkoxy) group , halogenated (C ₁ -C ₆ alkoxy) group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ alkylsulfinyl group, C ₁ -C ₆ alkylsulfonyl group, amino group, C ₁ -C ₆ alkylamino, di(C ₁ -C ₆ alkyl)amino, hydroxy(C ₁ -C ₆ alkyl)amino, N-(C ₁ -C ₆ alkyl)-N-hydroxyl (C ₁ -C ₆ alkyl)amino, formylamino, (C ₁ -C ₆ alkyl)carbonylamino, carboxyl, (C ₁ -C ₆ alkoxy)carbonyl, carbamoyl, (C ₁ -C ₆ alkyl Amino)carbonyl, di(C ₁ -C ₆ alkyl)aminocarbonyl, cyano, halo, phenyl, wherein the substituents represent substituted benzenes independently selected from 1-4 groups of substituent group α group, 5-membered or 6-membered aromatic heterocyclic group, wherein the substituent represents a substituted 5-membered or 6-membered aromatic heterocyclic group independently selected from 1-4 groups of substituent group α, 5-membered Or a 6-membered saturated heterocyclic group, wherein the substituent represents a substituted 5-membered or 6-membered saturated heterocyclic group, a 5-membered or 6-membered saturated heterocyclic group independently selected from 1-4 groups of substituent group α -(C ₁ -C ₆ alkyl) group, wherein the substituent represents a substituted 5-membered or 6-membered saturated heterocyclic ring independently selected from 1-4 groups of substituent group α-(C ₁ -C ₆ Alkyl) group, 5-membered or 6-membered saturated heterocyclyloxy group, wherein the substituent represents independently selected from substituent group α 1-4 substituted 5-membered or 6-membered saturated heterocyclyloxy groups, 5-membered or 6-membered saturated heterocyclylcarbonyl groups or wherein the substituents represent 1-4 groups independently selected from substituent group α A substituted 5- or 6-membered saturated heterocyclylcarbonyl group, and

Substituent group α represents C ₁ -C ₆ alkyl, hydroxyl (C ₁ -C ₆ alkyl) group, halogenated (C ₁ -C ₆ alkyl) group, (C ₃ -C ₈ cycloalkyl) -(C ₁ -C ₆ alkyl) group, C ₃ -C ₈ cycloalkyl group, hydroxyl group, C ₁ -C ₆ alkoxy group, halogenated (C ₁ -C ₆ alkoxy) group, C ₁ -C ₆ alkylamino, di(C ₁ -C ₆ alkyl)amino, carboxyl, (C ₁ -C ₆ alkoxy) carbonyl, carbamoyl, (C ₁ -C ₆ alkylamino) carbonyl, di (C ₁ -C ₆ alkyl)aminocarbonyl, cyano, halo and oxo.

(2) The compound according to (1) or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom, C ₁ -C ₆ alkyl, hydroxyl (C ₁ -C ₆ alkyl) group, (C ₁ - C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, [N-(C ₁ -C ₆ alkyl) -N-hydroxyl (C ₁ -C ₆ alkyl) amino] -(C ₁ -C ₆ alkyl) group, [N-(C ₁ -C ₆ alkyl)-N-(C ₁ -C ₆ alkyl)sulfonylamino]-(C ₁ -C ₆ alkyl) group, Carboxyl (C ₁ -C ₆ alkyl) group, halo (C ₁ -C ₆ alkyl) group, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ Cycloalkenyl, hydroxy, C ₁ -C ₆ alkoxy, hydroxy(C ₁ -C ₆ alkoxy) group, (C ₁ -C ₆ alkyl)sulfonyl-(C ₁ -C ₆ alkoxy ) group, carboxyl (C ₁ -C ₆ alkoxy) group, halogenated (C ₁ -C ₆ alkoxy) group, C ₁ -C ₆ alkylthio group, C ₁ -C ₆ alkyl Sulfonyl, N-(C ₁ -C ₆ alkyl)-N-hydroxyl(C ₁ -C ₆ alkyl)amino, (C ₁ -C ₆ alkylamino)carbonyl, di(C ₁ -C ₆ alkyl) ) aminocarbonyl, cyano or halo.

(3) The compound according to (1), or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom, C ₁ -C ₄ alkyl, hydroxyl (C ₁ -C ₄ alkyl) group, (C ₁ - C ₄ alkoxy)-(C ₁ -C ₄ alkyl) group, halogenated (C ₁ -C ₄ alkyl) group, C ₁ -C ₄ alkoxy, hydroxy (C ₁ -C ₆ alk oxy) group or (C ₁ -C ₄ alkyl)sulfonyl-(C ₁ -C ₄ alkoxy) group.

(4) The compound according to (1) or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁ -C ₄ alkyl, halogenated (C ₁ -C ₄ alkyl) group, C ₁ -C ₄ alkane Oxy or hydroxy(C ₁ -C ₆ alkoxy) group.

(5) The compound according to (1), or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁ -C ₄ alkyl.

(6) The compound according to (1), or a pharmaceutically acceptable salt thereof, wherein R ¹ is a halogenated (C ₁ -C ₄ alkyl) group.

(7) The compound according to (1), or a pharmaceutically acceptable salt thereof, wherein R ¹ is C ₁ -C ₄ alkoxy.

(8) The compound according to (1), or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydroxy(C ₁ -C ₆ alkoxy) group.

(9) The compound according to (1) or a pharmaceutically acceptable salt thereof, wherein R ¹ is a substituted phenyl group wherein the substituent represents 1-4 groups independently selected from substituent group α1, wherein the substituent Represents a substituted 5-membered or 6-membered aromatic heterocyclic group, 5-membered or 6-membered saturated heterocyclic group independently selected from 1-4 groups of substituent group α1, wherein the substituents represent independently selected from A substituted 5-membered or 6-membered saturated heterocyclic group of 1-4 groups in the substituent group α1, wherein the substituents represent substituted 5-membered or substituted 1-4 groups independently selected from the substituent group α1 6-membered saturated heterocyclyloxy or 5- or 6-membered saturated heterocyclylcarbonyl, and

The substituent group α1 represents a C ₁ -C ₆ alkyl group, a hydroxyl group, a carboxyl group and an oxo group.

(10) The compound according to (1) or a pharmaceutically acceptable salt thereof, wherein R ¹ is a 5-membered or 6-membered nitrogen-containing saturated heterocyclic group, wherein the substituent represents 1- independently selected from substituent group α2 A substituted 5-membered or 6-membered nitrogen-containing saturated heterocyclic group with 4 groups or a substituted 5-membered or 6-membered nitrogen-containing saturated heterocyclic group wherein the substituent represents 1-4 groups independently selected from substituent group α2 heterocyclyloxy, and

Substituent group α2 represents a C ₁ -C ₄ alkyl group and a hydroxyl group.

(11) The compound according to (1) or a pharmaceutically acceptable salt thereof, wherein

^R is substituted pyrrolidinyl, substituted piperidinyl, substituted piperazinyl, substituted thiomorpholinyl, substituted pyrrolidinyloxy or substituted piperidinyloxy, wherein pyrrolidinyl, The substituents of piperidinyl, piperazinyl, thiomorpholinyl, pyrrolidinyloxy and piperidinyloxy represent 1-2 groups independently selected from substituent group α3, and

Substituent group α3 represents a methyl group and a hydroxyl group.

(12) The compound according to (1) or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1 -[5-(4-Methylpiperazin-1-yl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol,

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(2-hydroxy Ethoxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol,

(-)-2-{1-[5-(4-carboxybutoxy)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluorocyclohexyl)-3-{ Fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol,

(-)-2-{1-[5-(4-carboxybutyl)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluorocyclohexyl)-3-{fluoro Substituting [4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol,

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1-[5- (Methylcarbamoyl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol,

(-)-4-(4,4-difluorocyclohexyl)-2-{1-[5-(dimethylcarbamoyl)pyrimidin-2-yl]piperidin-4-yl}-3-{ Fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol,

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1-[5- (Morpholin-4-yl-carbonyl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol,

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-(5-{[(2 -Hydroxyethyl)(methyl)amino]methyl}pyrimidin-2-yl)piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5 -alcohol,

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-{[(2S )-2-hydroxypropyl]oxy}pyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-alcohol,

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-(1-{5- [(1-Methylpiperidin-4-yl)oxy]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinolin-5-ol,

(-)-4-(4,4-difluorocyclohexyl)-2-[1-(5-{[(2S)-2,3-dihydroxypropyl]oxy}pyrimidin-2-yl)piper Pyridin-4-yl]-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5 -alcohol,

(-)-4-(4,4-difluorocyclohexyl)-2-[1-(5-{[(2R)-2,3-dihydroxypropyl]oxy}pyrimidin-2-yl)piper Pyridin-4-yl]-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5 -alcohol,

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-[1-(5- {[(3R)-1-Methylpyrrolidin-3-yl]oxy}pyrimidin-2-yl)piperidin-4-yl]-5,6,7,8-tetrahydroquinolin-5-ol ,

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-{[(2R )-2-hydroxypropyl]oxy}pyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-alcohol,

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(3-hydroxy -3-methylbutoxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol,

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(2-hydroxy-2-methyl Propoxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol,

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-(1 -{5-[3-(methylsulfonyl)propoxy]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinolin-5-ol,

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(3-hydroxy Propoxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol,

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1 -[5-(3,3,3-trifluoropropoxy)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol,

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5-[3-hydroxyl -2-(Hydroxymethyl)propoxy]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol ,

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5-[3-hydroxyl -2-(Hydroxymethyl)-2-methylpropoxy]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinone Lin-5-ol,

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-[1 -(5-{[methyl(methylsulfonyl)amino]methyl}pyrimidin-2-yl)piperidin-4-yl]-5,6,7,8-tetrahydroquinolin-5-ol,

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-[1-(5- {[Methyl(prop-2-ylsulfonyl)amino]methyl}pyrimidin-2-yl)piperidin-4-yl]-5,6,7,8-tetrahydroquinolin-5-ol,

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-[1 -(5-methylthiopyrimidin-2-yl)piperidin-4-yl]-5,6,7,8-tetrahydroquinolin-5-ol,

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1 -[5-(methylsulfonyl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol,

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5-[(2-hydroxyethyl) (Methyl)amino]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, and

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5-[(3S) -3-hydroxypyrrolidin-1-yl]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol.

(13) A pharmaceutical composition comprising the compound according to any one of (1) to (12) or a pharmaceutically acceptable salt thereof as an active ingredient.

(14) The pharmaceutical composition according to (13), which is used for the treatment or prevention of dyslipidemia, hypercholesterolemia, hypo-HDL cholesterolemia, hyper-HDL cholesterolemia, hypertriglyceridemia, arteriosclerosis, arteriosclerosis, Sclerosing heart disease, coronary heart disease, cerebrovascular disease, peripheral vascular disease, or obesity.

(15) The pharmaceutical composition according to (13), which is used for the treatment or prevention of dyslipidemia, low HDL cholesterolemia, arteriosclerosis or coronary heart disease.

(16) The pharmaceutical composition according to (13), which is used for treating or preventing hypo-HDL cholesterolemia.

(17) The pharmaceutical composition according to (13), which is used for treating or preventing arteriosclerosis.

(18) The pharmaceutical composition according to (13), which is used for treating or preventing a disease caused by a decrease in blood HDL cholesterol concentration.

(19) The pharmaceutical composition according to (13), which is used for treating or preventing a disease caused by an increase in the concentration of LDL cholesterol in blood.

(20) A CETP-inhibiting drug comprising the compound according to any one of (1) to (12) or a pharmaceutically acceptable salt thereof as an active ingredient.

(21) A drug for increasing HDL cholesterol concentration, comprising the compound according to any one of (1) to (12) or a pharmaceutically acceptable salt thereof as an active ingredient.

(22) A drug for lowering LDL cholesterol concentration, comprising the compound according to any one of (1) to (12) or a pharmaceutically acceptable salt thereof as an active ingredient.

Each group in the general formula (I) of the present invention has the following meanings.

"C ₁ -C ₆ alkyl" means straight chain or branched chain alkyl, which has 1-6 carbon atoms and may be, for example, methyl, ethyl, 1-propyl, 2-propyl, 1- Butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2- Butyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 2-ethyl- 1-butyl, 2,2-dimethyl-1-butyl or 2,3-dimethyl-1-butyl. The C ₁ -C ₆ alkyl group in R ¹ is preferably a C ₂ -C ₅ alkyl group, and most preferably 2-propyl, 1-pentyl or 2-methyl-1-propyl. The C ₁ -C ₆ alkyl group in the substituent group α is preferably a C ₁ -C ₄ alkyl group, more preferably a C ₁ -C ₂ alkyl group, and most preferably a methyl group.

"Hydroxy (C ₁ -C ₆ alkyl)" means the above-mentioned C ₁ -C ₆ alkyl substituted by 1 to 4 hydroxy groups and may be, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl , hydroxypentyl, hydroxyhexyl, dihydroxypropyl, dihydroxybutyl, dihydroxypentyl, dihydroxyhexyl, trihydroxybutyl, trihydroxypentyl, trihydroxyhexyl, tetrahydroxypentyl or tetrahydroxyhexyl, Hydroxy(C ₁ -C ₄ alkyl) is preferred, hydroxy(C ₁ -C ₂ alkyl) is more preferred, and hydroxymethyl is most preferred.

"(C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl)" means the above C ₁ -C ₆ alkyl substituted by one of the following C ₁ -C ₆ alkoxy and may be, For example, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, pentyloxymethyl, hexyloxymethyl, methoxyethyl, methoxypropyl, Methoxybutyl, methoxypentyl or methoxyhexyl, preferably (C ₁ -C ₄ alkoxy)-(C ₁ -C ₄ alkyl), more preferably (C ₁ -C ₄ alkoxy )-(C ₁ -C ₂ alkyl), and most preferably methoxymethyl, ethoxymethyl, 2-propoxymethyl or (2-methyl-1-propoxy)methyl.

"Hydroxy(C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl)" means the above C ₁ -C ₆ alkyl substituted by one of the following hydroxy (C ₁ -C ₆ alkoxy) and may be, for example, hydroxymethoxymethyl, hydroxyethoxymethyl, hydroxypropoxymethyl, hydroxybutoxymethyl, hydroxypentoxymethyl, hydroxyhexyloxymethyl, hydroxyethyl Oxyethyl, hydroxyethoxypropyl, hydroxyethoxybutyl, hydroxyethoxypentyl or hydroxyethoxyhexyl, preferably hydroxy(C ₁ -C ₄ alkoxy)-(C ₁ -C ₄ alkyl), more preferably hydroxy (C ₁ -C ₂ alkoxy)-(C ₁ -C ₂ alkyl).

"(C ₁ -C ₆ alkyl)amino-(C ₁ -C ₆ alkyl)" means the above C ₁ -C ₆ alkyl substituted by one of the following (C ₁ -C ₆ alkyl)amino groups and optionally is, for example, methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, pentylaminomethyl, hexylaminomethyl, methylaminoethyl, methylaminopropyl , methylaminobutyl, methylaminopentyl or methylaminohexyl, preferably (C ₁ -C ₄ alkyl)amino-(C ₁ -C ₄ alkyl), more preferably (C ₁ -C ₂ alkyl )amino-(C ₁ -C ₂ alkyl), and most preferably methylaminomethyl.

"Hydroxy(C ₁ -C ₆ alkyl)amino-(C ₁ -C ₆ alkyl)" means the above C ₁ -C ₆ alkyl substituted by one of the following hydroxy(C ₁ -C ₆ alkyl)amino and may be, for example, hydroxymethylaminomethyl, hydroxyethylaminomethyl, hydroxypropylaminomethyl, hydroxybutylaminomethyl, hydroxypentylaminomethyl, hydroxyhexylaminomethyl, hydroxyethyl Aminoethyl, hydroxyethylaminopropyl, hydroxyethylaminobutyl, hydroxyethylaminopentyl or hydroxyethylaminohexyl, preferably hydroxy(C ₁ -C ₄ alkyl)amino-(C ₁ -C ₄ alkyl), more preferably hydroxy(C ₁ -C ₂ alkyl)amino-(C ₁ -C ₂ alkyl).

"[N-(C ₁ -C ₆ alkyl)-N-hydroxyl (C ₁ -C ₆ alkyl) amino] -(C ₁ -C ₆ alkyl)" means that after one of the following N-(C ₁ -C ₆ alkyl)-N-hydroxy(C ₁ -C ₆ alkyl)amino substituted above C ₁ -C ₆ alkyl and may be, for example, (N-methyl-N-hydroxymethylamino)methyl Base, (N-methyl-N-hydroxyethylamino)methyl, (N-methyl-N-hydroxypropylamino)methyl, (N-methyl-N-hydroxybutylamino)methyl, (N-methyl-N-hydroxypentylamino)methyl, (N-methyl-N-hydroxyhexylamino)methyl, (N-methyl-N-hydroxyethylamino)ethyl, (N- Methyl-N-hydroxyethylamino)propyl, (N-methyl-N-hydroxyethylamino)butyl, (N-methyl-N-hydroxyethylamino)pentyl or (N-methyl -N-hydroxyethylamino)hexyl, preferably [N-(C ₁ -C ₄ alkyl)-N-hydroxyl (C ₁ -C ₄ alkyl)amino]-(C ₁ -C ₄ alkyl), more Preferably [N-(C ₁ -C ₂ alkyl)-N-hydroxyl(C ₁ -C ₂ alkyl)amino]-(C ₁ -C ₂ alkyl), and most preferably (N-methyl-N- Hydroxyethylamino) methyl.

"(C ₁ -C ₆ alkyl)sulfonylamino-(C ₁ -C ₆ alkyl)" means a group in which the above-mentioned C ₁ -C ₆ alkyl is substituted by an amino group and the amino group is further replaced by one of the following C ₁ -C ₆ alkylsulfonyl substituted and may be, for example, methylsulfonylaminomethyl, ethylsulfonylaminomethyl, propanesulfonylaminomethyl, butanesulfonylaminomethyl, pentanesulfonylaminomethyl , hexanesulfonylaminomethyl, methanesulfonylaminoethyl, methanesulfonylaminopropyl, methanesulfonylaminobutyl, methanesulfonylaminopentyl or methanesulfonylaminohexyl, preferably (C ₁ -C ₄ alkane group)sulfonylamino-(C ₁ -C ₄ alkyl), more preferably (C ₁ -C ₂ alkyl)sulfonylamino-(C ₁ -C ₂ alkyl).

"[N-(C ₁ -C ₆ alkyl)-N-(C ₁ -C ₆ alkyl)sulfonylamino]-(C ₁ -C ₆ alkyl)" represents a group in which the above (C ₁ The nitrogen atom of -C ₆ alkyl)sulfonylamino-(C ₁ -C ₆ alkyl) is substituted by one of the aforementioned C ₁ -C ₆ alkyl groups and may be, for example, (N-methyl-N-methylsulfonyl Amino)methyl, (N-methyl-N-ethanesulfonylamino)methyl, (N-methyl-N-propanesulfonylamino)methyl, (N-methyl-N-butanesulfonylamino) Methyl, (N-methyl-N-pentanesulfonylamino)methyl, (N-methyl-N-hexylsulfonylamino)methyl, (N-methyl-N-methylsulfonylamino)ethyl , (N-methyl-N-methylsulfonylamino)propyl, (N-methyl-N-methylsulfonylamino)butyl, (N-methyl-N-methylsulfonylamino)pentyl or ( N-methyl-N-methylsulfonylamino)hexyl, preferably [N-(C ₁ -C ₄ alkyl)-N-(C ₁ -C ₄ alkyl)sulfonylamino]-(C ₁ -C ₄ alkyl), more preferably [N-(C ₁ -C ₂ alkyl)-N-(C ₁ -C ₃ alkyl)sulfonylamino]-(C ₁ -C ₂ alkyl), and most preferably (N -methyl-N-methylsulfonylamino)methyl or [N-methyl-N-(2-propyl)sulfonylamino]methyl.

"Carboxyl (C ₁ -C ₆ alkyl)" means the above-mentioned C ₁ -C ₆ alkyl substituted by 1 or 2 carboxy groups and may be, for example, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl , carboxypentyl, carboxyhexyl, dicarboxypropyl, dicarboxybutyl, dicarboxypentyl or dicarboxyhexyl, preferably carboxyl (C ₁ -C ₄ alkyl), more preferably carboxyl (C ₃ -C ₄ alkyl ), and most preferably 4-carboxy-1-butyl.

"Halo(C ₁ -C ₆ alkyl)" means the above C ₁ -C ₆ alkyl substituted with 1 to 7 independently selected halo groups described below, and may be, for example, fluoromethyl, Difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, fluoroethyl, chloroethyl, bromoethyl, iodoethyl, difluoroethyl, trifluoroethyl , trichloroethyl, pentafluoroethyl, fluoropropyl, chloropropyl, fluorobutyl, trifluorobutyl, fluoropentyl or fluorohexyl. The halo(C ₁ -C ₆ alkyl) in R ¹ is preferably the halo(C ₁ -C ₄ alkyl) wherein the halo is 1-5 groups selected from fluoro and chloro, More preferred are halo(C ₂ -C ₄ alkyl) wherein halo is 1-5 fluoro groups, and most preferred is 4,4,4-trifluoro-1-butyl. Halo(C ₁ -C ₆ alkyl) in substituent group α is preferably halo(C ₁ -C ₄ alkyl) wherein the halo is 1 to 5 groups selected from fluoro and chloro ), more preferably halo(C ₁ -C ₂ alkyl) wherein the halo group is 1-5 fluoro groups.

"(C ₃ -C ₈ cycloalkyl)-(C ₁ -C ₆ alkyl)" means the above C ₁ -C ₆ alkyl substituted by one of the following C ₃ -C ₈ cycloalkyl and may be, for example , cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl group, cyclopropylpentyl or cyclopropylhexyl, preferably (C ₃ -C ₆ cycloalkyl)-(C ₁ -C ₄ alkyl), more preferably (C ₃ -C ₄ cycloalkyl)-(C ₁ -C ₂ alkyl).

"C ₂ -C ₆ alkenyl" means a linear or branched alkenyl group having 2 to 6 carbon atoms and one or more carbon-carbon double bonds and may be, for example, vinyl, propenyl ( For example, allyl), butenyl, pentenyl or hexenyl, preferably C ₂ -C ₅ alkenyl, more preferably C ₃ -C ₅ alkenyl, and most preferably 3-methyl-but- 1-en-1-yl.

"C ₂ -C ₆ alkynyl" means a straight or branched chain alkynyl having 2 to 6 carbon atoms and one or more carbon-carbon triple bonds and may be, for example, ethynyl, propynyl, butynyl Alkynyl, pentynyl or hexynyl and preferably C ₃ -C ₅ alkynyl.

"C ₃ -C ₈ cycloalkyl" means a cycloalkyl group having 3 to 8 carbon atoms and may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl , preferably C ₃ -C ₆ cycloalkyl, more preferably C ₃ -C ₄ cycloalkyl, and most preferably cyclopropyl.

"C ₃ -C ₈ cycloalkenyl" means a cycloalkenyl group having 3-8 carbon atoms and having one or more carbon-carbon double bonds and may be, for example, cyclopropenyl, cyclobutenyl, cyclopentene Cyclohexenyl, cycloheptenyl or cyclooctenyl, preferably C ₄ -C ₆ cycloalkenyl, and most preferably 1-cyclohexenyl.

"C ₁ -C ₆ alkoxy" represents a hydroxy group substituted by one of the above C ₁ -C ₆ alkyl groups and may be, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy or Hexyloxy. The C ₁ -C ₆ alkoxy in R ¹ is preferably methoxy, ethoxy, 2-propoxy, 2-methyl-1-propoxy or 3-methyl-1-butoxy. The C ₁ -C ₆ alkoxy group in the substituent group α is preferably a C ₁ -C ₄ alkoxy group, more preferably a C ₁ -C ₂ alkoxy group.

"Hydroxy (C ₁ -C ₆ alkoxy)" means the above-mentioned C ₁ -C ₆ alkoxy substituted with 1 to 4 hydroxy groups and may be, for example, hydroxymethoxy, hydroxyethoxy, hydroxypropoxy hydroxybutoxy, hydroxypentoxy, hydroxyhexyloxy, dihydroxypropoxy, dihydroxybutoxy, dihydroxypentoxy, dihydroxyhexyloxy, trihydroxybutoxy, trihydroxypentyl Oxy, trihydroxyhexyloxy, tetrahydroxypentyloxy or tetrahydroxyhexyloxy, preferably hydroxy (C ₂ -C ₆ alkoxy), and most preferably 2-hydroxyethoxy, 3-hydroxy-1- Propoxy, (2R)-2-hydroxy-1-propoxy, (2S)-2-hydroxy-1-propoxy, (2R)-2,3-dihydroxy-1-propoxy, ( 2S)-2,3-dihydroxy-1-propoxy, 2-hydroxy-2-methyl-1-propoxy, 3-hydroxy-2-(hydroxymethyl)-1-propoxy, 3 -Hydroxy-3-methyl-1-butoxy or 3-hydroxy-2-(hydroxymethyl)-2-methyl-1-propoxy.

"(C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkoxy)" represents the above C ₁ -C ₆ alkoxy substituted by one of the above C ₁ -C ₆ alkoxy and may be, For example, methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, pentyloxymethoxy, hexyloxymethoxy, methoxyethoxy , methoxypropoxy, methoxybutoxy, methoxypentyloxy or methoxyhexyloxy and preferably (C ₁ -C ₄ alkoxy)-(C ₁ -C ₄ alkoxy ).

"(C ₁ -C ₆ alkyl)sulfonyl-(C ₁ -C ₆ alkoxy)" means the above C ₁ -C ₆ alkoxy substituted by one of the following C ₁ -C ₆ alkylsulfonyl groups and Can be, for example, methylsulfonylmethoxy, ethylsulfonylmethoxy, propanesulfonylmethoxy, butanesulfonylmethoxy, pentylsulfonylmethoxy, hexylsulfonylmethoxy, methylsulfonyl Ethoxy, methylsulfonylpropoxy, methylsulfonylbutoxy, methylsulfonylpentyloxy or methylsulfonylhexyloxy, preferably (C ₁ -C ₄ alkyl)sulfonyl-(C ₁ -C ₄ alkoxy), more preferably (C ₁ -C ₂ alkyl)sulfonyl-(C ₁ -C ₃ alkoxy), and most preferably 3-methylsulfonyl-1-propoxy.

"Carboxyl (C ₁ -C ₆ alkoxy)" means the above-mentioned C ₁ -C ₆ alkoxy group substituted with 1 or 2 carboxyl groups and may be, for example, carboxymethoxy, carboxyethoxy, carboxypropoxy Carboxybutoxy, carboxypentyloxy, carboxyhexyloxy, dicarboxypropoxy, dicarboxybutoxy, dicarboxypentyloxy or dicarboxyhexyloxy, preferably carboxy(C ₂ -C ₅ alkane oxy), more preferably carboxy (C ₃ -C ₄ alkoxy), and most preferably 4-carboxy-1-butoxy.

"Halo(C ₁ -C ₆ alkoxy)" means the above C ₁ -C ₆ alkoxy group substituted with 1 to 7 independently selected halo groups below and may be, for example, fluoromethoxy Difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, fluoroethoxy, chloroethoxy, bromoethoxy, iodoethoxy Difluoroethoxy, trifluoroethoxy, trichloroethoxy, pentafluoroethoxy, fluoropropoxy, chloropropoxy, fluorobutoxy, fluoropentyloxy or fluorohexyloxy . The halo(C ₁ -C ₆ alkoxy) in R ¹ is preferably halo(C ₁ -C ₄ alkoxy) wherein the halo is 1-5 groups selected from fluoro and chloro ), more preferably halo(C ₁ -C ₃ alkoxy) wherein the halo group is 1-5 fluoro groups, and most preferably difluoromethoxy or 3,3,3-trifluoro-1 - Propoxy. Halo(C ₁ -C ₆ alkoxy) in substituent group α is preferably halo(C ₁ -C ₄ alkoxy) wherein halo is 1 to 5 groups selected from fluoro and chloro oxy), more preferably halo(C ₁ -C ₂ alkoxy) wherein the halo is 1-5 fluoro groups.

"C ₁ -C ₆ alkylthio" represents a mercapto group (-SH) substituted by one of the above C ₁ -C ₆ alkyl groups and may be, for example, methylthio, ethylthio, propylthio, butylthio, Pentylthio or hexylthio, preferably C ₁ -C ₄ alkylthio, more preferably C ₁ -C ₂ alkylthio, and most preferably methylthio.

"C ₁ -C ₆ alkylsulfinyl" represents a sulfinyl group (-SO-) substituted by one of the above-mentioned C ₁ -C ₆ alkyl groups and may be, for example, methylsulfinyl, ethylsulfinyl , propylsulfinyl, butylsulfinyl, pentylsulfinyl or hexylsulfinyl, preferably C ₁ -C ₄ alkylsulfinyl, more preferably C ₁ -C ₂ alkylsulfinyl.

"C ₁ -C ₆ alkylsulfonyl" means a sulfonyl group (-SO2-) substituted by one of the above C ₁ -C ₆ alkyl groups and may be, for example, methylsulfonyl, ethylsulfonyl, propanesulfonyl, butanesulfonyl, Sulfonyl, pentanesulfonyl or hexylsulfonyl, preferably C ₁ -C ₄ alkylsulfonyl, more preferably C ₁ -C ₂ alkylsulfonyl and most preferably methylsulfonyl.

"C ₁ -C ₆ alkylamino" means an amino group substituted by one of the aforementioned C ₁ -C ₆ alkyl groups and may be, for example, methylamino, ethylamino, propylamino, butylamino, pentylamino or Hexylamino, preferably C ₁ -C ₄ alkylamino, more preferably C ₁ -C ₂ alkylamino.

"Di(C ₁ -C ₆ alkyl)amino" means an amino group substituted by two independently selected above-mentioned C ₁ -C ₆ alkyl groups and may be, for example, dimethylamino, ethylmethylamino, methyl propylamino, butylmethylamino, methylpentylamino, hexylmethylamino, diethylamino, ethylpropylamino, butylethylamino, dipropylamino, butylpropylamino, dibutyl Amylamino, dipentylamino or dihexylamino, preferably di(C ₁ -C ₄ alkyl)amino, more preferably di(C ₁ -C ₂ alkyl)amino.

"Hydroxy(C ₁ -C ₆ alkyl)amino" means an amino group substituted by one of the aforementioned hydroxy(C ₁ -C ₆ alkyl) groups and may be, for example, hydroxymethylamino, hydroxyethylamino, hydroxypropylamino , Hydroxybutylamino, Hydroxypentylamino, Hydroxyhexylamino, Dihydroxypropylamino, Dihydroxybutylamino, Dihydroxypentylamino, Dihydroxyhexylamino, Trihydroxybutylamino, Trihydroxypentylamino, Trihydroxyhexylamino, tetrahydroxypentylamino or tetrahydroxyhexylamino and preferably hydroxy(C ₁ -C ₄ alkyl)amino.

"N-(C ₁ -C ₆ alkyl)-N-hydroxyl (C ₁ -C ₆ alkyl) amino" means that one of the above hydroxy (C ₁ -C ₆ alkyl) and one of the above C ₁ -C ₆ alkane and can be, for example, N-methyl-N-hydroxymethylamino, N-methyl-N-hydroxyethylamino, N-methyl-N-hydroxypropylamino, N-methyl -N-hydroxybutylamino, N-methyl-N-hydroxypentylamino, N-methyl-N-hydroxyhexylamino, N-ethyl-N-hydroxyethylamino, N-propyl-N- Hydroxyethylamino, N-butyl-N-hydroxyethylamino, N-pentyl-N-hydroxyethylamino or N-hexyl-N-hydroxyethylamino, preferably N-(C ₁ -C ₄ alkane base)-N-hydroxyl(C ₁ -C ₄ alkyl)amino, more preferably N-(C ₁ -C ₂ alkyl)-N-hydroxyl(C ₁ -C ₂ alkyl)amino, and most preferably N- Methyl-N-hydroxyethylamino.

"(C ₁ -C ₆ alkyl)carbonylamino" means a group in which a carbon atom of carbonylamino (-CONH-) is substituted by one of the above-mentioned C ₁ -C ₆ alkyl and may be, for example, methylcarbonylamino ( acetylamino), ethylcarbonylamino, propylcarbonylamino, butylcarbonylamino, pentylcarbonylamino or hexylcarbonylamino, preferably (C ₁ -C ₄ alkyl) carbonylamino, more preferably (C ₁ -C ₂ Alkyl)carbonylamino.

"(C ₁ -C ₆ alkoxy)carbonyl" means a carbonyl group (-CO-) substituted by one of the above C ₁ -C ₆ alkoxy groups and may be, for example, methoxycarbonyl, ethoxycarbonyl, propane Oxycarbonyl, butoxycarbonyl, pentyloxycarbonyl or hexyloxycarbonyl, preferably (C ₁ -C ₄ alkoxy)carbonyl, more preferably (C ₁ -C ₂ alkoxy)carbonyl. (C ₁ -C ₆ alkoxy)carbonyl in substituent group α is preferably (C ₁ -C ₄ alkoxy)carbonyl, more preferably (C ₁ -C ₂ alkoxy)carbonyl, and most preferably ethoxy carbonyl.

"(C ₁ -C ₆ alkylamino)carbonyl" represents a carbonyl group (-CO-) substituted by one of the aforementioned C ₁ -C ₆ alkylamino groups and may be, for example, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, Aminocarbonyl, butylaminocarbonyl, pentylaminocarbonyl or hexylaminocarbonyl, preferably (C ₁ -C ₄ alkylamino)carbonyl, more preferably (C ₁ -C ₂ alkylamino)carbonyl and most preferably methylamino carbonyl.

"Di(C ₁ -C ₆ alkyl)aminocarbonyl" means a carbonyl group (-CO-) substituted by one of the aforementioned di(C ₁ -C ₆ alkyl)amino groups and may be, for example, dimethylaminocarbonyl, ( N-ethyl-N-methylamino)carbonyl, (N-methyl-N-propylamino)carbonyl, (N-butyl-N-methylamino)carbonyl, (N-methyl-N-pentyl ylamino)carbonyl, (N-hexyl-N-methylamino)carbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, dibutylaminocarbonyl, dipentylaminocarbonyl or dihexylaminocarbonyl, preferably di( C ₁ -C ₄ alkyl)aminocarbonyl, more preferably di(C ₁ -C ₂ alkyl)aminocarbonyl and most preferably dimethylaminocarbonyl.

"Halo" may be fluorine, chlorine, bromine or iodine and is preferably fluorine, chlorine or bromine.

"5-membered or 6-membered aromatic heterocyclic group" means a 5-membered or 6-membered aromatic heterocyclic group containing 1 to 4 atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms and may be, for example, pyrrolyl , furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyran group, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, preferably 5-membered or 6-membered nitrogen-containing aromatic heterocyclic group, more preferably 5-membered nitrogen-containing aromatic heterocyclic group, and most preferably oxadiazolyl.

"5-membered or 6-membered saturated heterocyclic group" means a 5-membered or 6-membered saturated heterocyclic group containing 1-3 atoms selected from nitrogen atoms, oxygen atoms and sulfur atoms and may be, for example, pyrrolidinyl, Imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, dioxolanyl, dithiopentyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, Morpholinyl, thiomorpholinyl, dioxanyl, oxathianyl, dithianyl, trioxanyl or trithianyl, preferably 5-membered Or a 6-membered nitrogen-containing saturated heterocyclic group, more preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl. In the 5-membered or 6-membered nitrogen-containing saturated heterocyclic group, its nitrogen atom is preferably connected to the pyrimidinyl group in the general formula (I).

"5-membered or 6-membered saturated heterocyclic-(C ₁ -C ₆ alkyl)" means the above-mentioned C ₁ -C ₆ alkyl substituted by one of the above-mentioned 5-membered or 6-membered saturated heterocyclic group and may be, for example, pyrrole Alkylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl or thiomorpholinylmethyl, preferably 5-membered or 6-membered nitrogen-containing saturated heterocycle-(C ₁ -C ₄ alkane group), more preferably 5-membered or 6-membered nitrogen-containing saturated heterocycle-(C ₁ -C ₂ alkyl).

"5-membered or 6-membered saturated heterocyclic group oxy" means a hydroxyl group substituted with one of the above-mentioned 5-membered or 6-membered saturated heterocyclic group and may be, for example, pyrrolidinyloxy group, piperidinyloxy group, piperazinyl group Oxygen, morpholinyloxy or thiomorpholinyloxy, preferably 5- or 6-membered nitrogen-containing saturated heterocyclyloxy, more preferably pyrrolidinyloxy or piperidinyloxy. In a 5- or 6-membered saturated heterocyclyloxy group, the heteroatom of the heterocycle portion is not directly attached to the oxygen atom of the oxy portion.

"5-membered or 6-membered saturated heterocyclic carbonyl" means a carbonyl group (-CO-) substituted with one of the above-mentioned 5-membered or 6-membered saturated heterocyclic group and may be, for example, pyrrolidinylcarbonyl, piperidinylcarbonyl, piperidinylcarbonyl, An azinylcarbonyl group, a morpholinylcarbonyl group or a thiomorpholinylcarbonyl group, preferably a 5-membered or 6-membered nitrogen-containing saturated heterocyclylcarbonyl group, and most preferably a morpholinylcarbonyl group. In the 5-membered or 6-membered nitrogen-containing saturated heterocyclic carbonyl group, the nitrogen atom of the nitrogen-containing saturated heterocyclic group portion is preferably attached to the carbonyl portion.

In the case where the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has one or more asymmetric centers, carbon-carbon double bonds, axial chirality, etc., optical isomers may exist (including enantiomers and diastereomers), geometric isomers, tautomers and rotational isomers, and these isomers and mixtures thereof may be described by a single formula such as general formula (I). The present invention covers each of these isomers and mixtures in any proportions including racemates.

The compound represented by general formula (I) in the present invention covers the compound represented by general formula (I-1), (I-2), (I-3) or (I-4) or their mixture (including racemate) and diastereomeric mixtures) and preferably a compound represented by general formula (I-1) or (I-2) or a mixture thereof (including racemate), more preferably a compound represented by general formula (I-1).

The compound represented by the general formula (I-1) may contain a certain amount of the compound represented by the general formula (I-2), (I-3) or (I-4). The "compound represented by the general formula (I-1)" in the present invention covers "a compound of the general formula (I-1) containing a certain amount of the compound represented by the general formula (I-2), (I-3) or (I-4). 1) The compound represented by "and preferably covers the compound represented by the general formula (I-1) containing a certain amount of the compound represented by the general formula (I-2), " containing a certain amount of the compound represented by the general formula (I-3) "compound represented by general formula (I-1)" and "compound represented by general formula (I-1) containing a certain amount of compound represented by general formula (I-4)". In each case, the content percentage of the compound represented by the general formula (I-2), (I-3) or (I-4) in the compound represented by the general formula (I-1) may be, for example, 5% or less, preferably 3% or less, more preferably 1% or less, further preferably 0.5% or less, further more preferably 0.3% or less, particularly preferably 0.1% or less, and most preferably 0.05% or less less. For example, the peak area ratio or weight ratio in high performance liquid chromatography (HPLC) and the peak area ratio in the preferred HPLC can be used to calculate the formula (I-2), (I-3) or (I-4) to represent The above percentage content of the compound.

The compound of the present invention represented by general formula (I) can form an acid addition salt, and the acid addition salt thereof may be, for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, Oxalate, Malonate, Fumarate, Maleate, Phthalate, Trifluoroacetate, Methanesulfonate, Benzenesulfonate, p-Toluenesulfonic Acid salt, 2,4-dimethylbenzenesulfonate, 2,4,6-trimethylbenzenesulfonate, 4-ethylbenzenesulfonate or naphthalenesulfonate. The acid addition salts thereof are encompassed in the pharmaceutically acceptable salts of the present invention. The compounds of the present invention represented by general formula (I) can form acid addition salts with acids in any ratio and each of them (for example, monohydrochloride, dihydrochloride, etc.) or mixtures thereof are encompassed in the present invention .

In the case where the compound represented by the general formula (I) of the present invention has an acidic group, it can form a base addition salt and the base addition salt thereof can be, for example, a metal salt, an inorganic amine salt, an organic amine salt, or an amino acid Salt. The metal salt may be, for example, an alkali metal salt such as sodium, potassium, and lithium; an alkaline earth metal such as calcium and magnesium; aluminum; iron; zinc; copper; nickel; or cobalt. Inorganic amine salts can be, for example, ammonium salts. Organic amine salts can be, for example, morpholine salts, glucosamine salts, ethylenediamine salts, guanidinium salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, diethanolamine salts, piperazine salts or tetra Methyl ammonium salt. The amino acid salt can be, for example, a salt of glycinate, lysine, arginine, ornithine, glutamate or aspartate. The base addition salts thereof are encompassed in the pharmaceutically acceptable salts of the present invention.

The acid addition salt or base addition salt of the compound of the present invention represented by general formula (I) can be prepared by the following method, for example:

(i) dissolving the compound of the present invention represented by the general formula (I) in a solvent (for example, dichloromethane, acetone, ethyl acetate, etc.);

(ii) adding acid or base to the reaction solution and stirring the reaction mixture;

(iii) heating and cooling the reaction mixture, distilling the solvent, adding a poor solvent if necessary or seeding the desired salt compound; and

(iv) The precipitated solid was obtained by filtration.

In the case where the compound represented by the general formula (I) of the present invention has a group capable of forming an ester group such as a hydroxyl group or a carboxyl group, the compound can be converted into a pharmaceutically acceptable ester and the pharmaceutically acceptable ester is encompassed in In the present invention. The pharmaceutically acceptable ester of the compound represented by the general formula (I) may be a prodrug of the compound represented by the general formula (I) and is decomposed (for example, hydrolyzed) during metabolism when administered to a living body of a warm-blooded animal, To generate the compound represented by general formula (I).

The group that can form an ester group with a hydroxy group can be, for example, an aliphatic acyl group [for example, (C ₁ -C ₂₀ alkyl)carbonyl], an aromatic acyl group or an alkoxycarbonyl group [for example, (C ₁ -C ₆ alkyl) oxy)carbonyl]. The group which can form an ester group with a carboxyl group can be, for example, aliphatic alkyl [for example, C ₁ -C ₆ alkyl], alkylcarbonyloxyalkyl [for example, (C ₁ -C ₆ alkyl)carbonyl Oxy-(C ₁ -C ₆ alkyl)], cycloalkylcarbonyloxyalkyl [for example, (C ₃ -C ₈ cycloalkyl)carbonyloxy-(C ₁ -C ₆ alkyl)], Alkoxycarbonyloxyalkyl [for example, (C ₁ -C ₆ alkoxy) carbonyloxy-(C ₁ -C ₆ alkyl)] or cycloalkyloxycarbonyloxyalkyl [for example, ( C ₃ -C ₈ cycloalkyl)oxycarbonyloxy-(C ₁ -C ₆ alkyl)].

The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a hydrate or a solvate. Each of these or mixtures thereof are encompassed by the present invention.

The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof can form an isotopic compound in which one or more atoms constituting the compound are substituted by isotopic atoms in an unnatural ratio. Isotopic atoms may be radioactive or non-radioactive, eg, deuterium ( ² H; D), tritium ( ³ H; T), carbon-14 ( ¹⁴ C), iodine-125 ( ¹²⁵ I), and the like. Radioactive or non-radioactive isotope compounds can be used as drugs for treating or preventing diseases, reagents for research (eg, test reagents), diagnostic drugs (eg, imaging diagnostic drugs), and the like. The present invention encompasses radioactive or non-radioactive isotopic compounds.

"Dyslipidemia" in the present invention encompasses dyslipidemia. "Arteriosclerosis" encompasses (i) arteriosclerosis caused by various factors such as smoking or genetics (including multiple factors); Arteriosclerosis caused by lipid-related diseases, inflammatory diseases, diabetes, obesity or hypertensive diseases, and encompasses, for example, atherosclerosis, arteriolar sclerosis, occlusive arteriosclerosis and atherosclerosis. "Arteriosclerotic heart disease" means a cardiovascular disease due to arteriosclerosis as one of the causes. "Coronary heart disease"means cardiovascular disease due to arteriosclerosis as one of the etiologies or other diseases and covers, for example, heart failure, myocardial infarction, angina pectoris, myocardial ischemia, cardiovascular disorders or restenosis involving angioplasty. "Cerebrovascular disease" encompasses, for example, stroke or cerebral infarction. "Peripheral vascular disease" encompasses, for example, diabetic vascular complications.

The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be applied to, but not limited to, the treatment or prevention of (i) diseases caused by the decrease of HDL cholesterol concentration in blood, (ii) diseases caused by the decrease of HDL cholesterol concentration in blood A disease caused by an increase in LDL cholesterol concentration, and (iii) a disease treatable or preventable by inhibiting CETP activity other than the specific diseases as described above or below.

In the case where the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is used as a medicine, the compound may be combined with other medicines according to the use to form a pharmaceutical composition. The pharmaceutical composition may be (i) contain as active ingredient the

A combination of a preparation of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof and a preparation containing other drug as an active ingredient; or (ii) a single preparation (combined drug) containing the general formula ( Both the compound represented by I) or a pharmaceutically acceptable salt thereof and other drug as an active ingredient, and preferably a combination drug.

The pharmaceutical compositions can be administered simultaneously or separated by time intervals. In the case of divided administration of the pharmaceutical composition at time intervals, the dosage form is not particularly limited as long as it is a dosage form in which the pharmaceutical composition can be administered separately at different times. The time from the administration of one active ingredient to the administration of the other active ingredient is not particularly limited, and it is preferable to administer the other active ingredient within the time period in which the action of the previously administered active ingredient is still ongoing.

Other drugs that can be used in combination with the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof are not particularly limited as long as they are effective depending on the purpose thereof.

General formula (I), (I-1), (I-2), (I-3) or (I -4) Compounds (including compounds of each example) and intermediates for synthesizing them (including intermediates in each example or compounds of reference examples). Although the names of the compounds according to the above two nomenclatures may be different, each compound name correctly indicates the compound represented by the drawn chemical structural formula.

Can be prepared according to Method A (Methods A-1, A-2, A-3 and A-4), Method B (Methods B-1 and B-2), Method C, Method D, Method E or Method F described below The compound of the present invention represented by the general formula (I) [hereinafter also referred to as compound (I); same for other formulas].

Method A-1

Method A-2

Method A-3

Method A-4

Method B-1

Method B-2

Method C

Method D

Method E

Method F

In the structural formulas of the compounds in the above methods AF, R ¹ represents the same meaning as those in general formula (I); ^R represents C ₁ -C ₆ alkyl, hydroxy (C ₁ -C ₆ alkyl) group group, (C ₁ -C ₆ alkoxy)-(C ₁ -C ₆ alkyl) group, (C ₁ -C ₆ alkyl)sulfonyl-(C ₁ -C ₆ alkyl) group, carboxyl (C ₁ -C ₆ alkyl) group or halogenated (C ₁ -C ₆ alkyl) group; the group represented by formula R ^a O- represents C ₁ -C ₆ alkoxy, hydroxyl (C ₁ - C ₆ alkoxy) group, (C ₁ -C ₆ alkoxy) - (C ₁ -C ₆ alkoxy) group, (C ₁ -C ₆ alkyl) sulfonyl - (C ₁ -C ₆ alkoxy) group, carboxyl (C ₁ -C ₆ alkoxy) group or halo (C ₁ -C ₆ alkoxy) group, which is defined in R ¹ ; R ^b represents C ₁ - C ₆ alkyl; the group represented by the formula R ^b OCH ₂ - represents (C ₁ -C ₆ alkoxy) methyl, which covers the (C ¹ _{-C 6} alkoxy)-( C ₁ -C ₆ alkyl) group; R ^c represents C ₁ -C ₅ alkyl; R ^d represents C ₁ -C ₆ alkyl or C ₂ -C ₆ alkenyl, which is defined in R ¹ ; R ^e represents (C ₁ -C ₆ alkoxy) carbonyl, carbamoyl, (C ₁ -C ₆ alkylamino) carbonyl, di(C ₁ -C ₆ alkyl) aminocarbonyl, 5- or 6-membered saturated hetero Cyclic carbonyl or substituted 5-membered or 6-membered saturated heterocyclylcarbonyl as defined in R ¹ ; R ^f represents (C ₁ -C ₆ alkyl)aminomethyl, hydroxy(C ₁ -C ₆ alkyl)amino Methyl, [N-(C ₁ -C ₆ alkyl)-N-hydroxy(C ₁ -C ₆ alkyl) amino]methyl, (C ₁ -C ₆ alkyl)sulfonylaminomethyl or [N -(C ₁ -C ₆ alkyl)-N-(C ₁ -C ₆ alkyl) sulfonylamino] methyl, wherein each group in the above R ^f is respectively covered in (C ₁ -C ₆ alkyl) Amino-(C ₁ -C ₆ alkyl) group, hydroxy(C ₁ -C ₆ alkyl) amino-(C ₁ -C ₆ alkyl) group, [N-(C ₁ -C ₆ alkyl) -N-Hydroxy(C ₁ -C ₆ alkyl)amino]-(C ₁ -C ₆ alkyl) group, (C ₁ -C ₆ alkyl)sulfonylamino-(C ₁ -C ₆ alkyl) group or [N-(C ₁ -C ₆ alkyl)-N-(C ₁ -C ₆ alkyl)sulfonylamino]-(C ₁ -C ₆ alkyl) group, which are defined in R ¹ ; X ^a represents chloro, bromo, iodo, methanesulfonyloxy, trifluoromethanesulfonyloxy or p-toluenesulfonyloxy; X ^b represents chloro, bromo or iodo group; Boc represents tert-butoxycarbonyl; and P MB represents p-methoxybenzyl.

The acid used in the reaction of each step of the following methods A to F is not particularly limited as long as it does not inhibit the reaction and is selected from the group of acids described below. The group of acids includes organic acids such as acetic acid, propionic acid, trifluoroacetic acid or pentafluoropropionic acid; organic sulfonic acids such as p-toluenesulfonic acid, camphorsulfonic acid or trifluoromethanesulfonic acid; and inorganic acids such as hydrochloric acid, hydrobromic acid acid, hydroiodic acid, phosphoric acid, sulfuric acid or nitric acid.

The base used in the reaction of each step of the following methods A to F is not particularly limited as long as it does not inhibit the reaction and is selected from the group of bases described below. The group of bases includes alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate or potassium bicarbonate; alkali metal hydroxides such as hydroxide Lithium, sodium hydroxide, or potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide or barium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride, or potassium hydride; alkali metal amides such as lithium amide, sodium amide, or amide Potassium; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide; lithium alkylamides such as lithium diisopropylamide; alkali metal silylamides such as bistrimethylformazide lithium silylamide or sodium bistrimethylsilylamide; alkyllithium such as n-butyllithium, sec-butyllithium or tert-butyllithium; and organic amines such as triethylamine, tributylamine, diisopropylamine Ethylamine, N-methylmorpholine, pyridine, picoline, lutidine, 4-(N,N-dimethylamino)pyridine, 4-pyrrolidinopyridine, quinoline, N,N-di Methylaniline, 1,5-diazabicyclo[4,3,0]non-5-ene (DBN), 1,4-diazabicyclo[2,2,2]octane (DABCO) or 1 , 8-diazabicyclo[5,4,0]undec-7-ene (DBU).

The solvent used for the reaction of each step of the methods A to F described below is not particularly limited as long as it does not inhibit the reaction and partially dissolves the starting material and, for example, is selected from a group of solvents described below. The group of solvents includes aliphatic hydrocarbons such as hexane (e.g., n-hexane), pentane (e.g., n-pentane), heptane (e.g., n-heptane), petroleum ether, or cyclohexane; aromatic hydrocarbons such as benzene, Toluene, xylene or ethylbenzene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyl Tetrahydrofuran, 1,4-dioxane, dimethoxyethane or diglyme; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone; esters such as Methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate or butyl acetate; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; carboxylic acids such as acetic acid or propionic acid; alcohols such as methanol, ethanol, 1 - propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol (tert-butanol) or 1,2-propanediol; Amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, dimethylimidazolone or hexamethylphosphoric triamide; sulfoxides such as Dimethyl sulfoxide; sulfones such as sulfolane; water; and mixtures thereof.

In the reaction of each step of the following methods A-F, the reaction temperature varies depending on the solvent, starting material, reagent, etc., and the reaction time varies depending on the solvent, starting material, reagent, reaction temperature, etc.

In the reaction of each step of the following methods A-F, after the reaction is completed, the desired compound in each step can be isolated from the reaction mixture according to a method well known in the field of organic chemistry. For example, by (i) filtering off insoluble raw materials such as a catalyst if necessary, (ii) adding water and a water-immiscible solvent (e.g., dichloromethane, diethyl ether, ethyl acetate, etc.) to the reaction mixture and extracting the desired compound, (iii) washing the organic layer with water and drying it with a desiccant such as anhydrous magnesium sulfate, and (iv) distilling off the solvent to obtain the desired compound. The obtained desired compound can be further purified by methods well known in the field of organic chemistry (for example, recrystallization, reprecipitation, silica gel column chromatography, etc.) if necessary. In addition, unpurified desired compounds in the respective processes can also be used in the next reaction.

In the case where a compound as a starting material in the reaction of each step of the following methods A to F has a group such as an amino group, a hydroxyl group, and a carboxyl group that inhibits a desired reaction, a protecting group for such a group can be appropriately introduced and when necessary The introduced protecting group can be removed. Such protecting group is not particularly limited as long as it is a commonly used protecting group and may be, for example, Greene's Protecting Group in T.W.Greene, P.G.Wuts, Organic Synthesis, 4th Edition, 2007, John Wiley & Sons, Inc., etc. Protecting groups described in . The introduction reaction of such a protecting group and the removal reaction of a protecting group can be performed according to methods well known in the field of organic chemistry (for example, as described in the above-mentioned documents).

In the reaction of each step of the following methods A-F (steps A-5 to A-14 in method A), a mixture of two diastereomers (4 kinds of enantiomers) can be obtained by column chromatography, crystallization, etc. mixture) to separate single diastereomers (racemates) and optically active compounds (for example, optically active carboxylic acid compounds or optically active amine compounds) etc. by optically active column chromatography, fractional crystallization, A single enantiomer is separated from a single diastereomer (racemate). A single enantiomer can be separated from a mixture of two diastereomers (a mixture of 4 enantiomers) by optically active column chromatography at any step.

In each of the examples shown below in Methods A-F, a single diastereomer (racemate) was isolated from a mixture of two diastereomers in step A-7 and a single diastereomer was isolated in step A-10. Separation of individual enantiomers in enantiomers (racemates). Compounds (10), (11) and (12) are single diastereomers (racemates) described in Reference Examples 7, 8 and 9, respectively and Compound (13) is described in Reference Example 10 single enantiomer. Compounds (14), (15), (17), (18), (20), (22), (24), (25), (26), (Ia), (Ib) prepared from compound (13) ), (Ic), (Id), (Ie), (If) and (I) are single enantiomers.

Separation of single diastereomers (racemates) and separation of single enantiomers are not limited to the above examples and may be carried out in any process (same or different process) of methods A-F, respectively. For example, without separation of a single diastereomer (racemate) in step A-7, a mixture of two diastereomers can be used as starting material to carry out steps A-8 to A-9 respectively , Steps A-11 to A-14, Steps B-1 to B-4, Steps C-1 to C-2, Steps D-1 to D-2, Steps E-1 to E-3, or Step F-1 . In the case where separation of a single diastereomer (racemate) is carried out in any of the above steps, the subsequent steps can be carried out separately using the single diastereomer (racemate) as a starting material. In the case where the separation of the single enantiomer is further carried out in any of the above steps, the subsequent steps can be carried out separately using the single enantiomer as a starting material and obtain compound (I) as a single enantiomer [preferred compound (I-1)]. In the case where only a single diastereomer (racemate) is separated in any of the above steps, compound (I) is obtained as a single diastereomer (racemate) by further separation of the single enantiomer and compound (I) as a single enantiomer [preferably compound (I-1)]. In the absence of separation of single diastereomers (racemates) and separation of single enantiomers in any of the above steps, by carrying out separation of single diastereomers (racemates) Separation from the single enantiomer yields compound (I) as a mixture of two diastereomers and compound (I) as a single enantiomer [preferably compound (I-1)].

Hereinafter, the reactions of the respective steps of methods A-F are described.

(Method A)

Method A is a method for preparing compounds (Ia) and (Ib) encompassed in compound (I).

(step A-1)

Step A-1 is a step of preparing compound (2) by reducing compound (1). Compound (1) is known.

The reducing agent to be used is not limited as long as it can be used in the reduction reaction of alkoxycarbonyl to formyl and is preferably diisobutylaluminum hydride.

The solvent to be used is preferably an aromatic hydrocarbon, and more preferably toluene.

The reaction temperature is preferably -100°C to 0°C.

The reaction time is preferably 30 minutes to 12 hours.

(Step A-2)

Step A-2 is a step of preparing compound (4) by reacting compound (3) with acetonitrile in the presence of a base. Compound (3) is known.

Protecting groups well known in the field of organic chemistry can be used instead of tert-butoxycarbonyl as the protecting group for the amino group in compound (3) (for example, T.W.Greene, P.G.Wuts, Greene's Protecting Groups in Organic Synthesis, Fourth Edition, 2007, John Wiley & Sons, Inc.).

The base to be used is preferably lithium alkylamide, more preferably lithium diisopropylamide.

The solvent to be used is preferably aliphatic hydrocarbons, aromatic hydrocarbons, ethers or mixtures thereof, more preferably n-heptane, ethylbenzene, tetrahydrofuran or mixtures thereof.

The reaction temperature is preferably -78°C-50°C.

The reaction time is preferably 30 minutes to 48 hours.

(step A-3)

Step A-3 is a step of preparing compound (6) by reacting compounds (2) and (4), and then reacting compound (5). Compound (5) is known. Compound (5) may be employed in excess in Step A-3.

The solvent to be used is preferably an aromatic hydrocarbon, more preferably toluene.

The reaction temperature is preferably 50°C to 150°C.

The reaction time is preferably 30 minutes to 48 hours.

(step A-4)

Step A-4 is a step of producing compound (7) by oxidizing compound (6).

The oxidizing agent to be used is not limited as long as it can be used for the oxidation reaction of dihydropyridyl to pyridyl, and is preferably 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).

The solvent to be used is preferably a halogenated hydrocarbon, more preferably dichloromethane.

The reaction temperature is preferably 0°C-50°C.

The reaction time is preferably 30 minutes to 12 hours.

(step A-5)

Step A-5 is a step of producing compound (8) by reducing compound (7).

The reducing agent to be used is not limited as long as it can be used in the reduction reaction of cyano group to formyl group and is preferably diisobutylaluminum hydride.

The solvent to be used is preferably an aromatic hydrocarbon, more preferably toluene.

The reaction temperature is preferably -100°C to 0°C.

The reaction time is preferably 30 minutes to 12 hours.

(step A-6)

Step A-6 is a step of producing compound (9) by reacting compound (8) with p-methoxybenzyl bromide in the presence of a base.

The base to be used is not limited as long as it can be used for the alkylation reaction of the hydroxyl group and is preferably an alkali metal hydride, more preferably sodium hydride.

The solvent to be used is preferably an amide, more preferably N,N-dimethylformamide.

The reaction temperature is preferably -50°C to 50°C.

The reaction time is preferably 30 minutes to 12 hours.

In Step A-6, protecting groups well known in the field of organic chemistry can be used instead of the p-methoxybenzyl group as the protecting group for the hydroxyl group (e.g., T.W. Greene, P.G. Wuts, Greene's Protecting Groups in Organic Synthesis, Fourth Edition, 2007, John Wiley & Sons, Inc.).

(step A-7)

Step A-7 is a step of preparing compound (10) by reacting compound (9) with 4-trifluoromethylphenylmagnesium bromide. 4-Trifluoromethylphenyl magnesium bromide can be prepared from 4-trifluoromethylphenyl bromide and magnesium by methods well known in the art of organic chemistry.

The solvent to be used is preferably ether, more preferably tetrahydrofuran.

The reaction temperature is preferably -20°C to 50°C.

The reaction time is preferably 30 minutes to 12 hours.

In step A-7, compound (10) has two asymmetric carbon atoms (the carbon atom to which the hydroxyl group or p-methoxybenzyloxy group is attached) and can be used as a mixture of stereoisomers (4 optical isomers A mixture of , ie, a mixture of diastereomers) was obtained. Depending on the nature of the mixture, the diastereomeric mixture obtained in Step A-7 can be separated into individual diastereomeric compounds. Such separation can be achieved by methods well known in the art of organic chemistry (eg, resolution of diastereomeric mixtures by column chromatography or fractional crystallization). Depending on the nature of the compound, each isolated diastereomeric compound (mixture of enantiomers) can be separated into a single enantiomeric compound. Such separation can be carried out by methods well known in the art of organic chemistry (for example, optical resolution by column chromatography or fractional crystallization to form diastereomeric salts). In Step A-7, the same is true for the compound obtained by using protecting groups other than p-methoxybenzyloxy and tert-butoxycarbonyl as the two protecting groups in compound (9). This is the same with respect to compound (11) obtained in Step A-8.

(step A-8)

Step A-8 is a step of preparing compound (11) by reacting compound (10) with a fluorinating agent.

The fluorinating agent to be used is not limited as long as it can be used for the fluorination reaction of the hydroxyl group and is preferably trifluorobis(methoxyethyl)aminosulfur [Deoxo-Fluor (trade name)].

The solvent to be used is preferably a halogenated hydrocarbon, more preferably dichloromethane.

The reaction temperature is preferably -100°C to 0°C.

The reaction time is preferably 30 minutes to 24 hours.

(step A-9)

Step A-9 is a step of producing compound (12) by reacting compound (11) with zinc bromide.

The solvent to be used is preferably a halogenated hydrocarbon, more preferably dichloromethane.

The reaction temperature is preferably 0°C to 50°C.

The reaction time is preferably 1 hour to 5 days.

The diastereomeric mixture obtained in Step A-9 can be separated into single diastereomeric compounds and compound (12) can be obtained as single diastereomeric compounds.

The tert-butoxycarbonyl removal reaction in Step A-9 can also be carried out by methods well known in the field of organic chemistry (e.g., T.W. Greene, P.G. Wuts, Greene's Protecting Groups in Organic Synthesis, Fourth Edition, 2007, John Wiley & Sons, Inc.).

(Step A-10)

Step A-10 is a step of optically resolving compound (12) by optically active column chromatography to obtain compound (13) as a single enantiomer.

The optically active column and resolution conditions to be used are not limited as long as they can achieve optical resolution of compound (12) and those described in Reference Example 10 are preferred.

(Step A-11)

Step A-11 is a step of preparing compound (14) by reacting compound (13) with 5-bromo-2-chloropyrimidine in the presence of a base.

The base to be used is preferably an organic amine, more preferably diisopropylethylamine or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).

The solvent to be used is preferably ether or amide, more preferably 1,4-dioxane.

The reaction temperature is preferably 20°C-150°C.

The reaction time is preferably 30 minutes to 12 hours.

(Step A-12)

Step A-12 is a step of preparing compound (15) by reacting compound (14) with morpholine in the presence of a palladium catalyst, a phosphorus reagent and a base.

The palladium catalyst to be used is not limited as long as it can be used for the amination reaction on the aromatic ring and can be, for example, in J. Tsuji, Palladium Reagents and Catalysis: A New Perspective in the 21st Century, 2004, John Wiley & Sons, Inc., etc. The palladium catalyst described in . The palladium catalyst to be used is preferably tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), palladium(II) chloride, palladium(II) acetate or dichlorobis(triphenylene phosphine)palladium(II), more preferably palladium(II) acetate.

The phosphorus reagent to be used is not limited as long as it can be used for the amination reaction on the aromatic ring and preferably 2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, 2-bis Cyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H- [1,4']bipyrazole, cyclohexylphosphine, 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene or 2-( Diphenylphosphino)-2'-(N,N-dimethylamino)biphenyl, more preferably 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

The base to be used is preferably an alkali metal alkoxide, more preferably sodium tert-butoxide.

The solvent to be used is preferably an aromatic hydrocarbon, an alcohol or a mixture thereof, more preferably toluene, 2-methyl-2-propanol or a mixture thereof.

The reaction temperature is preferably 20°C to 150°C.

The reaction time is preferably 30 minutes to 12 hours.

In step A-12, an optionally substituted 5-membered or 6-membered nitrogen-containing saturated cyclic amine other than morpholine is used instead of morpholine for amination reaction. The palladium catalyst used for this amination reaction is preferably tris(dibenzylideneacetone)dipalladium(0) and is preferably stirred under microwave irradiation. According to a method similar to the method of step B-4, by removing the p-methoxybenzyl group in the compound obtained in the above reaction, the compound wherein ^R in the compound (I) is an optionally substituted 5-membered or 6-membered A nitrogen-containing saturated heterocyclic group and a nitrogen atom attached to the 5-position of pyrimidine.

In step A-12, a compound represented by the formula R ^g B(OH) ₂ or its borate ester can be used instead of morpholine for carbon-carbon coupling reaction, wherein R ^g represents C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, phenyl, substituted phenyl, 5-membered or 6-membered aromatic heterocyclic group or substituted 5-membered or 6-membered aromatic heterocyclic group as defined in R ¹ . The palladium catalyst used in this carbon-carbon coupling reaction is preferably palladium(II) acetate. The compound wherein R ¹ is R ^g in compound (I) can be prepared by removing the p-methoxybenzyl group in the compound obtained in the above reaction according to a method similar to that of Step B-4.

(Step A-13)

Step A-13 is a step of preparing compound (Ia) by treating compound (15) with an acid.

The acid to be used is preferably a mineral acid, more preferably hydrochloric acid.

The solvent to be used is preferably ether, alcohol or a mixture thereof, more preferably 1,4-dioxane, methanol or a mixture thereof.

The reaction temperature is preferably 20°C to 150°C.

The reaction time is preferably 30 minutes to 6 hours.

(Step A-14)

Step A-14 is a step of preparing compound (Ib) by reacting compound (Ia) with compound (16) in the presence of a base.

The base to be used is preferably an alkali metal carbonate, more preferably cesium carbonate.

The solvent to be used is preferably ether or amide, more preferably tetrahydrofuran, N,N-dimethylformamide or 1-methyl-2-pyrrolidone.

The reaction temperature is preferably from 0°C to 100°C.

The reaction time is preferably 30 minutes to 50 hours.

(Method B)

Method B is a method for preparing compound (Ic) encompassed in compound (I).

(step B-1)

Step B-1 is a step of producing compound (17) by reacting compound (13) with 2-chloro-5-formylpyrimidine in the presence of a base.

The base to be used is preferably an organic amine, more preferably 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).

The solvent to be used is preferably an amide, more preferably 1-methyl-2-pyrrolidone.

The reaction temperature is preferably from 0°C to 100°C.

The reaction time is preferably 30 minutes to 12 hours.

(Step B-2)

Step B-2 is a step of producing compound (18) by reducing compound (17).

The reducing agent to be used is not limited as long as it can be used for the reduction of formyl group to hydroxyl group and is preferably alkali metal borohydride such as sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and lithium borohydride, more Sodium borohydride is preferred.

The solvent to be used is preferably ether, alcohol or a mixture thereof, more preferably tetrahydrofuran, ethanol or a mixture thereof.

The reaction temperature is preferably -20°C to 50°C.

The reaction time is preferably 10 minutes to 6 hours.

(step B-3)

Step B-3 is a step of preparing compound (20) by reacting compound (18) with methanesulfonyl chloride in the presence of a base, followed by reaction with compound (19). Compound (19) is known.

The base to be used is preferably an organic amine, more preferably diisopropylethylamine.

The solvent to be used is preferably a halogenated hydrocarbon, more preferably dichloromethane.

The reaction temperature is preferably from 0°C to 100°C.

The reaction time is preferably 10 minutes to 6 hours.

(step B-4)

Step B-4 is a step of preparing compound (Ic) by removing p-methoxybenzyl group in compound (20) in the presence of anisole and an acid.

The acid to be used is preferably an organic acid, more preferably trifluoroacetic acid.

The solvent to be used is preferably a halogenated hydrocarbon, more preferably dichloromethane.

The reaction temperature is preferably from 0°C to 100°C.

The reaction time is preferably 30 minutes to 48 hours.

The removal of the methoxybenzyl group can also be carried out in Step B-4 by methods well known in the field of organic chemistry (for example, T.W.Greene, P.G.Wuts, Greene's Protecting Groups in Organic Synthesis, Fourth Edition, 2007, John Wiley & Sons, Inc.).

(Method C)

Method C is a method for preparing compound (I).

(step C-1)

Step C-1 is a step of preparing compound (22) by reacting compound (13) with compound (21) in the presence of a base. Compound (21) is known and can be easily prepared from known compounds or according to Reference Examples. Step C-1 can also be carried out similarly to those of Step A-12, using a palladium catalyst, a phosphorus reagent and a base.

The base to be used is preferably an organic amine, more preferably diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) or a mixture thereof.

The solvent to be used is preferably ether, alcohol or amide, more preferably 1,4-dioxane, 2-propanol, 2-methyl-2-propanol, N,N-dimethylformamide or 1 -Methyl-2-pyrrolidone.

The reaction temperature is preferably 20-160°C.

The reaction time is preferably 30 minutes to 12 hours.

Step C-1 is carried out under microwave irradiation.

(step C-2)

Step C-2 is a step of preparing compound (I) by removing p-methoxybenzyl group in compound (22) in the presence of anisole and an acid.

Step C-2 is performed according to a method similar to that of step B-4.

(Method D)

Method D is a production method of compound (Id) encompassed in compound (I).

(step D-1)

Step D-1 is a step of preparing compound (24) by reacting compound (17) with compound (23). Compound (23) is known or can be easily prepared from known compounds.

The solvent to be used is preferably ether, more preferably tetrahydrofuran.

The reaction temperature is preferably 0°C-60°C.

The reaction time is preferably 10 minutes to 6 hours.

(step D-2)

Step D-2 includes

(Step D-2A) a step of removing the p-methoxybenzyl group in compound (24) in the presence of an acid; and

(Step D-2B) A step of preparing compound (Id) by subjecting the compound obtained in step D-2A to dehydration reaction or reduction reaction.

The p-methoxybenzyl removal reaction and dehydration reaction can be carried out simultaneously. The acid used for the reaction is preferably an inorganic acid or an organic acid, more preferably hydrochloric acid or trifluoroacetic acid.

The solvent to be used is preferably a halogenated hydrocarbon or ether, more preferably dichloromethane or 1,4-dioxane.

The reaction temperature is preferably from 0°C to 110°C.

The reaction time is preferably 30 minutes to 48 hours.

The reducing agent used for the reduction reaction is not limited as long as it can be used for the reduction reaction of the hydroxyl group and is preferably triethylsilane.

The removal of the methoxybenzyl group can also be carried out in Step D-2 by methods well known in the field of organic chemistry (for example, T.W.Greene, P.G.Wuts, Greene's Protecting Groups in Organic Synthesis, Fourth Edition, 2007, John Wiley & Sons, Inc.).

(method E)

Method E is a preparation method of compound (Ie) encompassed in compound (I).

(step E-1)

Step E-1 is a step of preparing compound (25) by oxidizing compound (17).

The oxidizing agent to be used is not limited as long as it can be used for the oxidation of formyl to carboxyl and is preferably potassium permanganate, sodium chlorite, sodium hypochlorite, hydrogen peroxide, chromic acid, m-chloroperbenzoic acid, silver nitrate or dichromic acid Pyridinium, more preferably sodium chlorite. In the case where sodium chlorite is used as the oxidizing agent, it is preferable to use 2-methyl-2-butene and sodium dihydrogenphosphate in combination.

The solvent to be used is preferably ether, alcohol, water or a mixture thereof, more preferably tetrahydrofuran, t-butanol, water or a mixture thereof.

The reaction temperature is preferably 0°C to 70°C.

The reaction time is preferably 30 minutes to 6 hours.

(step E-2)

Step E-2 is a step of preparing compound (26) by reacting compound (25) with an alcohol compound or an amine compound in the presence of a condensing agent.

The condensing agent to be used is not limited as long as it can be used for the condensation reaction of carboxyl group and hydroxyl group or amino group and is preferably 1,1'-carbonyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimides or their combination with 1-hydroxybenzotriazole.

Bases can be used in combination with the above-mentioned condensing agents. The base to be used is preferably an organic amine, more preferably triethylamine.

The solvent to be used is preferably ether, nitrile, amide or a mixture thereof, more preferably tetrahydrofuran, acetonitrile, N,N-dimethylacetamide or a mixture thereof.

The reaction temperature is preferably from 0°C to 120°C.

The reaction time is preferably 30 minutes to 6 hours.

(step E-3)

Step E-3 is a step of preparing compound (Ie) by removing p-methoxybenzyl group in compound (26) in the presence of anisole and an acid.

Step E-3 can be performed according to a method similar to that of step B-4.

(Method F)

Method F is a production method of compound (If) encompassed in compound (I).

(step F-1)

Step F-1 consists of

(Step F-1A) a step of removing p-methoxybenzyl group in compound (17) in the presence of anisole and acid; and

(Step F-1B) A step of preparing compound (If) by reacting the compound obtained in step F-1A with an amine compound in the presence of a reducing agent.

(Step F-1A)

Step F-1A can be performed according to a method similar to that of step B-4.

(Step F-1B)

The reducing agent to be used is not limited as long as it can be used for the reductive amination reaction of the formyl group and is preferably sodium triacetoxyborohydride or sodium borohydride.

The solvent to be used is preferably ether, alcohol or a mixture thereof, more preferably tetrahydrofuran, methanol or a mixture thereof.

The reaction temperature is preferably from 0°C to 60°C.

The reaction time is preferably 30 minutes to 14 hours.

_wherein R ¹ is [N-(C _{1 -C 6} Alkyl)-N-(C ₁ -C ₆ alkyl)sulfonylamino]methyl compounds.

When the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is used as a medicine, it can (i) itself be used as a bulk powder; Orally prepared preparations such as tablets, capsules, granules, powders or syrups prepared by mixing acceptable excipients, diluents, etc.; give. Oral administration is preferred.

These formulations are prepared by well-known methods using additives such as excipients, binders, disintegrants, lubricants, emulsifiers, stabilizers, flavoring agents, diluents or solvents for injection.

Excipients can be, for example, organic or inorganic excipients. Organic excipients can be, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; chain starch etc. Inorganic excipients can be, for example, silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicates; sulfates such as calcium sulfate, and the like.

The binder may be, for example, the compounds shown in the above excipients; gelatin; polyvinylpyrrolidone; polyethylene glycol and the like.

The disintegrant can be, for example, the compounds shown in the above excipients; chemically modified starch or cellulose derivatives such as croscarmellose sodium or carboxymethyl starch sodium; crospovidone and the like.

The lubricant can be, for example, talc; silica gel; waxes such as beeswax or sperm whale; glycols; D,L-leucine; sulfates such as sodium sulfate;

The emulsifier may be, for example, colloidal clay such as bentonite or begum; anionic surfactant such as sodium lauryl sulfate; cationic surfactant such as benzalkonium chloride; nonionic surfactant such as polyoxyethylene alkyl ether, and the like.

Stabilizers can be, for example, parabens such as methylparaben; alcohols such as chlorobutanol; benzalkonium chloride; phenols;

Flavoring agents can be, for example, commonly used sweeteners, acidulants, spices and the like.

The diluent can be, for example, water, ethanol, propylene glycol, and the like.

Solvents for injection may be, for example, water, ethanol, glycerin and the like.

The dose of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient of the present invention varies depending on the symptoms, age, etc. of the patient. According to the symptoms, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof can be administered to adults 1-6 times a day, with 0.01 mg/kg (preferably 0.05 mg/kg) as the lower limit and 500 mg/kg orally (preferably 50 mg/kg) as the upper limit, or 0.001 mg/kg (preferably 0.005 mg/kg) as the lower limit and 50 mg/kg (preferably 5 mg/kg) as the upper limit for parenteral administration.

Effect of the present invention

In terms of CETP inhibitory activity, increasing effect on HDL cholesterol concentration, reducing effect on LDL cholesterol concentration, rapid onset of pharmacological effects, prolonged pharmacological effects, physical stability, solubility, oral absorption, blood drug concentration , cell membrane permeability, metabolic stability, tissue migration, bioavailability (BA), drug-drug interaction, toxicity, etc., the compound represented by the general formula (I) of the present invention or its pharmaceutically acceptable The salt of has excellent properties and is used as a medicine for warm-blooded animals, especially humans. Above-mentioned medicine is treatment or prevention, preferably dyslipidemia, hypercholesterolemia, low HDL cholesterolemia, high HDL cholesterolemia, hypertriglyceridemia, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease (comprising heart failure , myocardial infarction, angina pectoris, myocardial ischemia, cardiovascular disorders and restenosis associated with angioplasty), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (including diabetic vascular complications) or obesity, More preferably dyslipidemia, low HDL cholesterolemia, high HDL cholesterolemia, arteriosclerosis, arteriosclerotic heart disease or coronary heart disease, further preferably dyslipidemia, low HDL cholesterolemia, arteriosclerosis or coronary heart disease and even more preferably low Medications for HDL cholesterol or arteriosclerosis

The mode of realizing the present invention

Hereinafter, the present invention is further explained with examples, reference examples, test examples and formulation examples. However, the scope of the present invention is not limited therein. Although the bonds between the following fluorine groups or hydroxyl groups and carbon atoms can be represented by the planar structural formulas in the chemical structural formulas in the following examples and reference examples, respectively, each compound represented by the name of the compound including (+) or (-) The compound is a single enantiomer prepared using the intermediate compound of Reference Example 10 as a single enantiomer.

Although the compounds of Examples 2, 7, 12, 13, 30, 32, 33, 35, 38, 41, 44, 52, 56 and 58 are not represented by compound names including (+) or (-), each compound is a single enantiomer prepared using the intermediate compound of Reference Example 10 as a single enantiomer. The chemical structural formulas in parentheses represent the chemical structural formulas of the reaction intermediates in the respective Examples or Reference Examples.

The following abbreviations are used in Examples and Reference Examples.

Boc: tert-butoxycarbonyl

PMB: p-methoxybenzyl

TBS: tert-butyldimethylsilyl

Example

(Example 1)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-[1 -(pyrimidin-2-yl)-piperidin-4-yl]-5,6,7,8-tetrahydroquinolin-5-ol

To 1.28 g (1.70 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl) prepared by a method similar to that of Reference Example 15 ) phenyl] methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-[1-(pyrimidin-2-yl)piperidin-4-yl ]-5,6,7,8-tetrahydroquinoline in 8ml of 1,4-dioxane was added to 4ml of 6N hydrochloric acid, and the reaction solution was stirred at 70°C for 3 hours. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. To the obtained residue was added n-heptane, and a precipitate was obtained by filtration to obtain 0.93 g of the title compound as a white solid (yield: 86%).

Specific rotation: [α] _D ²³ = -120° (C = 0.13, methanol).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δppm: 8.22 (2H, d, J = 5Hz), 7.66 (2H, d, J = 8Hz), 7.39 (2H, d, J = 8Hz), 7.23 ( 1H, d, J = 47Hz), 6.39 (1H, t, J = 5Hz), 5.13 (1H, dt, J = 6, 6Hz), 4.87-4.72 (1H, m), 4.57-4.43 (1H, m) , 3.72-3.56(1H, m), 2.91-2.55(4H, m), 2.37-1.45(15H, m), 1.13(3H, s), 0.99(3H, s), 0.71-0.55(1H, m) .

Mass Spectrum (EI, m/z): 632[M ⁺ ].

(Example 2)

2-[1-(5-bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl) Phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

To 1.0 g (1.5 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl) prepared by a method similar to that of Reference Example 10 ) phenyl] methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8 -Tetrahydroquinoline in 5ml N, the solution in N-dimethylformamide was added 0.58g (3.0mmol) 5-bromo-2-chloropyrimidine and 0.27ml (1.8mmol) 1,8-diazabicyclo[ 5.4.0]-7-undecene, the reaction solution was stirred at 100°C for 3 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. A 5% ethyl acetate/n-hexane solution was added to the resulting residue and a precipitate was obtained by filtration to give 0.78 g of 2-[1-(5-bromopyrimidin-2-yl)piperidin-4-yl as a white solid ]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy ]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline (yield: 64%).

To 63 mg (0.076 mmol) of 2-[1-(5-bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro [4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydro A solution of quinoline in 0.5 ml of 1,4-dioxane was added with 1 ml of methanol and 0.2 ml of concentrated hydrochloric acid, and the reaction solution was stirred at 50°C for 7 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography [n-hexane/ethyl acetate=70/30 (V/V)] to obtain 46 mg of the title compound as a white solid (yield: 85%).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.21 (2H, s), 7.64 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.21 (1H, d, J = 45Hz), 5.12(1H, q, J=6Hz), 4.66-4.77(1H, m), 4.38-4.49(1H, m), 3.68-3.55(1H, m), 2.85-2.60(4H, m), 2.38-2.21(2H, m), 2.19-2.04(4H, m), 1.98-1.48(9H, m), 1.15(3H, s), 1.01(3H, s), 0.68-0.58(1H, m).

(Example 3)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-methoxypyrimidine -2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

To 100 mg (0.15 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl) prepared by a method similar to that of Reference Example 10 ) phenyl] methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8 -Tetrahydroquinoline 64 mg (0.44 mmol) of 2-chloro-5-methoxypyrimidine and 1 ml of 1,4-dioxane were added, and the reaction solution was stirred at 80° C. for 26.6 hours. After the reaction was completed, 0.5 ml of 6N hydrochloric acid was added to the reaction solution, and the mixture was stirred at 50°C for 8 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=4/1 (V/V)], and the fractions containing the desired compound were concentrated under reduced pressure. n-Hexane was added to the obtained residue, and a precipitate was obtained by filtration to obtain 44 mg of the title compound as a white powder (yield: 45%).

Specific rotation: [α] _D ²⁷ = -85° (C = 0.13, methanol).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 8.04 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.20 (1H, d, J = 48Hz), 5.12(1H, dt, J=6, 6Hz), 4.72-4.6l(1H, m), 4.44-4.32(1H, m), 3.77(3H, s), 3.71-3.54(1H, m) , 2.91-2.57(4H, m), 2.39-1.61(15H, m), 1.15(3H, s), 1.00(3H, s), 0.70-0.56(1H, m).

Mass spectrum (EI, m/z): 662 [M ⁺ ].

(Example 4)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidine-2 -yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

To 4.30 g (5.13 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl) prepared by a method similar to that of Reference Example 12 ) phenyl] methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-{1-[5-(morpholin-4-yl)pyrimidine- 2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinoline was added with 14ml of concentrated hydrochloric acid, 36ml of methanol and 40ml of 1,4-dioxane, and the reaction solution was stirred at 70°C 1.5 hours. After the reaction was completed, the reaction solution was poured into 200 ml of a saturated aqueous sodium bicarbonate solution to which 14 ml of a 6N aqueous sodium hydroxide solution had been added and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=3/1-2/1 (V/V)], and fractions containing the desired compound were concentrated under reduced pressure. Toluene was added to the obtained residue, and a precipitate was obtained by filtration to obtain 2.60 g of the title compound as a white solid (yield: 78%).

Specific rotation: [α] _D ²⁸ = -49° (C = 0.30, chloroform).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δppm: 7.92 (2H, s), 7.66 (2H, d, J = 8Hz), 7.39 (2H, d, J = 8Hz), 7.23 (1H, d, J=47Hz), 5.80(1H, brs), 5.12(1H, dt, J=6, 6Hz), 4.68-4.53(1H, m), 4.39-4.23(1H, m), 3.74-3.55(1H, m ), 2.93-2.50(4H, m), 2.37-1.42(15H, m), 1.10(3H, s), 0.97(3H, s), 0.65-0.52(1H, m).

Mass spectrum (EI, m/z): 648 [M ⁺ ].

(Example 5)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1 -[5-(morpholin-4-yl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol

To 100 mg (0.120 mmol) of (-)-2-[1-(5-bromopyrimidin-2-yl)piperidin-4-yl]-4-(4 , 4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7- Add 21 mg (0.24 mmol) morpholine, 14 mg (0.048 mmol) (2-biphenyl) di-tert-butylphosphine to a solution of dimethyl-5,6,7,8-tetrahydroquinoline in 0.6 ml toluene, 23mg (0.24mmol) sodium tert-butoxide and 11mg (0.012mmol) tris(dibenzylideneacetone) dipalladium (0), the reaction solution was stirred at 60°C for 50 minutes, while using a microwave reactor (product name: initiator (Initiator), manufactured by Biotage) for microwave irradiation. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=80/20-50/50 (V/V)] to obtain 89 mg of 4-(4,4-difluorocyclohexyl as an orange solid )-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-{ 1-[5-(morpholin-4-yl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinoline (yield: 88%).

89 mg (0.11 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methyl) obtained above Oxybenzyl)oxy]-7,7-dimethyl-2-{1-[5-(morpholin-4-yl)pyrimidin-2-yl]piperidin-4-yl}-5,6 , A solution of 7,8-tetrahydroquinoline in 1.8ml 1,4-dioxane was added to 0.9ml 4N hydrogen chloride-1,4-dioxane solution, and the reaction solution was stirred at 50°C for 5 hours . After the reaction was completed, saturated aqueous sodium bicarbonate solution was poured into the reaction solution under ice-cooling, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=70/30-50/50 (V/V)], and the fractions containing the desired compound were concentrated under reduced pressure. n-Hexane was added to the obtained solid, and the insoluble matter was obtained by filtration to obtain 63 mg of the title compound as a white solid (yield: 83%).

Specific rotation: [α] _D ²³ = -74° (C = 0.12, chloroform).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.04 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.21 (1H, d, J = 46Hz), 5.15-5.08(1H, m), 4.73-4.63(1H, m), 4.44-4.35(1H, m), 3.84(4H, t, J=5Hz), 3.67-3.56(1H, m), 2.96(4H, t, J=5Hz), 2.84-2.59(4H, m), 2.36-1.50(15H, m), 1.15(3H, s), 1.00(3H, s), 0.67-0.59(1H, m ).

Mass spectrum (FAB, m/z): 717[M ⁺ ].

(Example 6)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1 -[5-(piperidin-1-yl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol

Except replacing morpholine with piperidine and from 100 mg (0.120 mmol) (-)-2-[1-(5-bromopyrimidin-2-yl)piperidine-4 prepared by a method similar to that of Reference Example 11 -Base]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl) Oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, except for starting with those of the first step of Example 5 and Example 7, gave 41 mg of The title compound as a beige solid (Yield: 48%).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.06 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.20 (1H, d, J = 48Hz), 5.16-5.08(1H, m), 4.71-4.60(1H, m), 4.43-4.33(1H, m), 3.68-3.56(1H, m), 2.92(4H, t, J=5Hz), 2.84-2.60(4H, m), 2.36-1.48(21H, m), 1.15(3H, s), 1.01(3H, s), 0.67-0.59(1H, m).

Specific rotation: [α] _D ²³ = -70° (C = 0.12, chloroform).

Mass Spectrum (FAB, m/z): 715[M ⁺ ].

(Example 7)

4-(4,4-difluorocyclohexyl)-2-(1-{5-[4-(ethoxycarbonyl)piperidin-1-yl]pyrimidin-2-yl}piperidin-4-yl) -3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

To 98 mg (0.11 mmol) of 4-(4,4-difluorocyclohexyl)-2-(1-{5-[4-(ethoxycarbonyl)piperene) prepared by a method similar to that of Reference Example 13 Pyridin-1-yl]pyrimidin-2-yl}piperidin-4-yl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxy Benzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline solution in 2ml ethanol was added 1ml4N hydrogen chloride/1,4-dioxane solution, in The reaction solution was stirred at 50°C for 3 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution was poured into the reaction solution under ice-cooling, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=90/10-60/40 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 69 mg of The title compound as a brown solid (Yield: 81%).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.05 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.21 (1H, d, J = 53Hz), 5.15-5.08(1H, m), 4.72-4.62(1H, m), 4.44-4.34(1H, m), 4.16(2H, q, J=7Hz), 3.67-3.56(1H, m), 3.34-3.25(2H, m), 2.83-2.59(6H, m), 2.41-1.52(20H, m), 1.26(3H, t, J=7Hz), 1.14(3H, s), 1.00(3H, s ), 0.66-0.60 (1H, m).

Mass Spectrum (FAB, m/z): 787[M ⁺ ].

(Embodiment 8)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1 -[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol

Using 1-methylpiperazine instead of morpholine and from 120 mg (0.144 mmol) of (-)-2-[1-(5-bromopyrimidin-2-yl)piperazine prepared by a method similar to that of Reference Example 11 Pyridin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxy Benzyl)oxyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline start, carry out reactions similar to those of the first step of Example 5 and Example 7, 36 mg of the title compound were obtained as a pale yellow solid (yield: 34%).

Specific rotation: [α] _D ²³ = -61° (C = 0.13, chloroform).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.06 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.21 (1H, d, J = 47Hz), 5.18-5.06(1H, m), 4.73-4.60(1H, m), 4.46-4.33(1H, m), 3.67-3.55(1H, m), 3.01(4H, t, J=4Hz), 2.91-2.49(4H, m), 2.57(4H, t, J=4Hz), 2.41-1.51(15H, m), 2.34(3H, s), 1.14(3H, s), 1.00(3H, s), 0.69-0.58(1H, m).

Mass Spectrum (FAB, m/z): 730[M ⁺ ].

(Example 9)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1 -[5-(thiomorpholin-4-yl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol

Except that thiomorpholine was used instead of ethyl isopiperidine and 120 mg (0.144 mmol) of (-)-2-[1-(5-bromopyrimidine-2- Base) piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4- Starting with methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, reactions similar to those of Reference Example 13 and Example 7 were carried out to give 61 mg of the title compound as a white solid (yield: 58%).

Specific rotation: [α] _D ²³ = -64° (C = 0.22, chloroform).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.03 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.21 (1H, d, J = 52Hz), 5.15-5.07(1H, m), 4.74-4.64(1H, m), 4.46-4.36(1H, m), 3.67-3.57(1H, m), 3.22(4H, t, J=5Hz), 2.84-2.58(8H, m), 2.36-1.52(15H, m), 1.14(3H, s), 1.00(3H, s), 0.67-0.60(1H, m).

Mass Spectrum (FAB, m/z): 733[M ⁺ ].

(Example 10)

(-)-4-(4,4-difluorocyclohexyl)-2-{1-[5-(1,1-dioxythiomorpholin-4-yl)pyrimidin-2-yl]piperidine-4- Base}-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

Except that thiomorpholine 1,1-dioxide was used instead of ethyl isopiperidine and 100 mg (0.120 mmol) (-)-2-[1-( 5-bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl} -5-[(4-methoxybenzyl)oxyl group]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline start, carry out similarly to reference example 13 and embodiment Those of 7 were reacted to obtain 54 mg of the title compound as a pale yellow solid (yield: 59%).

Specific rotation: [α] _D ²⁴ = -67° (C = 0.22, chloroform).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.08 (2H, s), 7.64 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.21 (1H, d, J = 44Hz), 5.16-5.08(1H, m), 4.76-4.66(1H, m), 4.48-4.38(1H, m), 3.68-3.57(1H, m), 3.51(4H, t, J=5Hz), 3.16(4H, t, J=5Hz), 2.84-2.58(4H, m), 2.36-1.52(15H, m), 1.15(3H, s), 1.01(3H, s), 0.67-0.59(1H, m ).

(Example 11)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(4-hydroxy Piperidin-1-yl)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

Except that 4-hydroxypiperidine and 1,2-methoxyethane were used instead of ethyl isopiperidine and toluene and 150 mg (0.180 mmol) of (-)- 2-[1-(5-bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl) Starting with phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, proceed similarly to reference Reaction of those of Example 13 and Example 7 gave 55 mg of the title compound as a pale yellow solid (yield: 42%).

Specific rotation: [α] _D ²⁵ = -58° (C = 0.14, chloroform).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.06 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.21 (1H, d, J = 47Hz), 5.16-5.07(1H, m), 4.72-4.61(1H, m), 4.44-4.34(1H, m), 3.86-3.74(1H, m), 3.69-3.56(1H, m), 3.29- 3.20(2H, m), 2.86-2.58(6H, m), 2.36-1.48(20H, m), 1.15(3H, s), 1.00(3H, s), 0.68-0.58(1H, m).

Mass Spectrum (FAB, m/z): 731[M ⁺ ].

(Example 12)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1-[5- (Propan-2-yl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol

96 mg (0.14 mmol) of (-)-4- (4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7, 7-Dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, except starting from the first steps similar to those of Example 2 and Example 38 The reaction gave 47 mg of the title compound as a white solid (yield: 50%).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.14 (2H, s), 7.64 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.21 (1H, d, J = 45Hz), 5.12(1H, q, J=6Hz), 4.80-4.69(1H, m), 4.52-4.41(1H, m), 3.68-3.56(1H, m), 2.84-2.58(4H, m), 2.34-2.05(6H, m), 1.97-1.48(10H, m), 1.20(6H, d, J=7Hz), 1.15(3H, s), 1.00(3H, s), 0.67-0.58(1H, m ).

(Example 13)

4-(4,4-difluorocyclohexyl)-2-[1-(5-ethoxypyrimidin-2-yl)piperidin-4-yl]-3-{fluoro[4-(trifluoromethyl Base) phenyl] methyl} -7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

To 50 mg (0.077 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)benzene prepared by a method similar to that of Example 4 Base] methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline- Add 75 mg (0.23 mmol) cesium carbonate and 12 μl (0.15 mmol) iodoethane to a solution of 5-alcohol in 1.0 ml N,N-dimethylformamide, and stir the reaction solution at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography [n-hexane/ethyl acetate=70/30 (V/V)] to obtain 45 mg of the title compound as a white solid (yield: 85%).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.03 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.21 (1H, d, J = 47Hz), 5.12(1H, q, J=6Hz), 4.71-4.59(1H, m), 4.43-4.32(1H, m), 3.97(2H, q, J=7Hz), 3.68-3.55(1H, m ), 2.85-2.58(4H, m), 2.36-2.02(6H, m), 2.00-1.56(9H, m), 1.37(3H, t, J=7Hz), 1.15(3H, s), 1.01(3H , s), 0.67-0.58 (1H, m).

(Example 14)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1 -[5-(prop-2-yloxy)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol

Except that iodoisopropane was used instead of iodoethane and the reaction temperature was set to 50°C and from 60 mg (90 μmol) of (-)-4-(4,4-difluorocyclohexyl) prepared by a method similar to that of Example 4 )-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7- Except starting with dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, reactions similar to those of Example 13 were carried out to obtain 54 mg of the title compound as a white solid (yield: 90%).

Specific rotation: [α] _D ²⁴ = -68° (C = 0.26, chloroform).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.01 (2H, s), 7.63 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.21 (1H, d, J = 46Hz), 5.12(1H, q, J=6Hz), 4.73-4.61(1H, m), 4.46-4.33(1H, m), 4.25(1H, septet, J=6Hz), 3.70-3.56(1H, m ), 2.91-2.58(4H, m), 2.36-2.04(6H, m), 2.00-1.59(9H, m), 1.29(6H, d, J=6Hz), 1.15(3H, s), 1.01(3H , s), 0.70-0.57 (1H, m).

(Example 15)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(2-hydroxy Ethoxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

Except that (2-bromomethoxy)(tert-butyl)dimethylsilane was used instead of ethyl iodide and the reaction temperature was set at 50°C and from 61 mg (94 μmol) of (-) -4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl) Piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, except starting, reactions similar to those of Example 13 afforded 68 mg of 2-{ 1-[5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4- Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5- alcohol.

To the 68 mg (84 μmol) of 2-{1-[5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)pyrimidin-2-yl]piperidine-4 obtained above -Base}-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6, To a solution of 7,8-tetrahydroquinolin-5-ol in 0.5 ml of tetrahydrofuran was added 0.13 ml (0.13 mmol) of 1N tetrabutylammonium fluoride/tetrahydrofuran solution, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography [n-hexane/ethyl acetate=50/50 (V/V)] to obtain 52 mg of the title compound as a white solid (yield: 89%).

Specific rotation: [α] _D ²⁴ = -70° (C = 0.17, chloroform).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.06 (2H, s), 7.63 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.21 (1H, d, J = 47Hz), 5.12(1H, q, J=7Hz), 4.72-4.63(1H, m), 4.44-4.33(1H, m), 4.02(2H, t, J=5Hz), 3.92(2H, brs), 3.68-3.56(1H, m), 2.84-2.58(4H, m), 2.39-1.54(16H, m), 1.15(3H, s), 1.01(3H, s), 0.70-0.58(1H, m). (Example 16)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-[1 -(5-pentylpyrimidin-2-yl)piperidin-4-yl]-5,6,7,8-tetrahydroquinolin-5-ol

100 mg (0.148 mmol) of (-)-4-(4,4- Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl -2-(Piperidin-4-yl)-5,6,7,8-Tetrahydroquinoline, except starting, carried out reactions similar to those of the first step of Example 2 and Example 38 to obtain 95 mg of The title compound as a white solid (Yield: 91%).

Specific rotation: [α] _D ²⁴ = -71° (C = 0.17, chloroform).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.08 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.21 (1H, d, J = 46Hz), 5.12(1H, q, J=6Hz), 4.82-4.68(1H, m), 4.53-4.41(1H, m), 3.68-3.55(1H, m), 2.94-2.58(4H, m), 2.45-1.48(19H, m), 1.36-1.21(4H, m), 1.14(3H, s), 1.00(3H, s), 0.88(3H, t, J=7Hz), 0.70-0.57(1H, m ).

Mass Spectrum (ES, m/z): 703[M ⁺ ].

(Example 17)

(-)-2-[1-(5-cyanopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-( Trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

Except that 5-bromo-2-chloropyrimidine was replaced by 2-chloropyrimidine-5-carbonitrile synthesized by the method described in A. Takamizawa et al., Journal of Organic Chemistry, 1964, volume 29, pages 1740-1742 and obtained from similar 78 mg (0.12 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methanol prepared by referring to the method of Example 10 Base}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline Except for the initiation, reactions similar to those of the first step of Example 2 and Example 38 were carried out. 60 mg of the title compound were obtained as a white solid (yield: 79%).

Specific rotation: [α] _D ²⁴ = -81° (C = 0.21, chloroform).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.42 (2H, s), 7.65 (2H, d, J = 8Hz), 7.38 (2H, d, J = 8Hz), 7.23 (1H, d, J = 47Hz), 5.21-5.07(1H, m), 4.95-4.82(1H, m), 4.68-4.54(1H, m), 3.71-3.55(1H, m), 2.93-2.74(3H, m), 2.63( 1H, d, J=17Hz), 2.38-1.59(15H, m), 1.15(3H, s), 1.01(3H, s), 0.77-0.62(1H, m).

Mass spectrum (FAB, m/z): 658[(M+1) ⁺ ].

(Example 18)

(-)-2-{1-[5-(cyclohex-1-en-1-yl)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluorocyclohexyl) -3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

To 78 mg (0.094 mmol) of 2-{1-[5-(cyclohex-1-en-1-yl)pyrimidin-2-yl]piperidin-4- Base}-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy Base]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline was added with 0.4ml of 6N hydrochloric acid and 2ml of 1,4-dioxane, and the reaction solution was stirred at 80°C for 3 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-80/20 (V/V)], and fractions containing the desired compound were concentrated under reduced pressure. Diethyl ether was added to the resulting residue, and a precipitate was obtained by filtration to obtain 45 mg of the title compound as a white solid (yield: 67%).

Specific rotation: [α] _D ²⁵ = -110° (C = 0.050, methanol).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δ: 8.27 (2H, s), 7.66 (2H, d, J = 8Hz), 7.39 (2H, d, J = 8Hz), 7.22 (1H, d, J=47Hz), 5.99-5.93(1H, m), 5.13(1H, dt, J=6, 6Hz), 4.84-4.70(1H, m), 4.55-4.42(1H, m), 3.72-3.56(1H , m), 2.93-2.54 (4H, m), 2.38-1.55 (23H, m), 1.13 (3H, s), 0.99 (3H, s), 0.69-0.57 (1H, m).

Mass Spectrum (EI, m/z): 712[M ⁺ ].

(Example 19)

(-)-2-[1-(5-cyclopropylpyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4- (Trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

To 100 mg (0.12 mmol) of (-)-2-[1-(5-bromopyrimidin-2-yl)piperidin-4-yl]-4-(4 , 4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7- A solution of dimethyl-5,6,7,8-tetrahydroquinoline in 1.2ml of toluene was added with 31mg (0.36mmol) cyclopropyl boronic acid, 0.1ml water and 127mg (0.60mmol) tripotassium phosphate, and then 38 µl (0.024 mmol) of 20% cyclohexylphosphine-toluene solution and 3.0 mg (0.012 mmol) of palladium acetate were added under atmosphere, and the reaction solution was stirred at 100°C for 6.8 hours. After stirring under heating, 38 μl (0.024 mmol) of 20% cyclohexylphosphine-toluene solution, 3.0 mg (0.012 mmol) of palladium acetate and 10 mg (0.12 mmol) of cyclopropylboronic acid were added, and the reaction solution was stirred at 100° C. for 3.5 hours. After stirring under heating, add 11 mg (0.024 mmol) of 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl and 7.0 mg (0.012 mmol) of bis(dibenzylideneacetone) palladium (0), and the reaction solution was further stirred at 100° C. for 5.5 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-70/30 (V/V)] twice and the fraction containing the desired compound was concentrated under reduced pressure.

To the resulting 25 mg residue were added 1 ml of 1,4-dioxane and 50 µl of 6N hydrochloric acid, and the reaction solution was stirred at 60°C for 1.5 hours, at room temperature for 13 hours, and at 60°C for 5 hours. After stirring under heating, 50 µl of 6N hydrochloric acid was added thereto, and the reaction solution was further stirred at 60°C for 3.5 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-70/30 (V/V)], and the fractions containing the desired compound were concentrated under reduced pressure. Diisopropyl ether and n-hexane were added to the obtained residue, and a precipitate was obtained by filtration to obtain 22 mg of the title compound as a white solid (yield: 27%).

Specific rotation: [α] _D ²⁵ = -76° (C = 0.045, methanol).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δ: 8.04 (2H, s), 7.65 (2H, d, J = 8Hz), 7.38 (2H, d, J = 8Hz), 7.22 (1H, d, J=48Hz), 5.13(1H, dt, J=6, 6Hz), 4.78-4.66(1H, m), 4.48-4.38(1H, m), 3.72-3.56(1H, m), 2.89-2.55(4H , m), 2.36-1.55 (16H, m), 1.13 (3H, s), 0.99 (3H, s), 0.89-0.83 (2H, m), 0.67-0.50 (3H, m).

Mass Spectrum (EI, m/z): 672[M ⁺ ].

(Example 20)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-[5-(hydroxymethyl )pyrimidin-2-yl]piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-alcohol

To 94 mg (0.12 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methanol prepared by a method similar to that of Reference Example 16 Base}-2-[1-(5-formylpyrimidin-2-yl)piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl -5.0 mg (0.13 mmol) of sodium borohydride was added to a solution of 5,6,7,8-tetrahydroquinoline in 0.6 ml of ethanol, and the reaction solution was stirred at 0° C. for 2 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution was poured into the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=100/0-60/40 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 89 mg of 4-( 4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-[5-(hydroxymethyl)pyrimidin-2-yl] piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline.

89 mg (0.11 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-[5 -(Hydroxymethyl)pyrimidin-2-yl]piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7, 8-Tetrahydroquinoline was added with 0.5 ml of 1,4-dioxane, 0.5 ml of water and 0.5 ml of 4N hydrogen chloride-1,4-dioxane solution, and the reaction solution was stirred at 50°C for 6 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=100/0-50/50 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 41 mg as white The title compound as a solid (Yield: 54%).

Specific rotation: [α] _D ²⁴ = -81° (C = 0.15, chloroform).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.23 (2H, s), 7.64 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.21 (1H, d, J = 46Hz), 5.16-5.06(1H, m), 4.84-4.74(1H, m), 4.56-4.44(1H, m), 4.46(2H, s), 3.71-3.54(1H, m), 2.88-2.69( 3H, m), 2.63(1H, d, J=17Hz), 2.37-1.50(16H, m), 1.14(3H, s), 1.00(3H, s), 0.70-0.57(1H, m).

Mass spectrum (FAB, m/z): 663[(M+1) ⁺ ].

(Example 21)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1 -[5-(2-Methylpropoxy)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol

To 55 mg (0.085 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)benzene prepared by a method similar to that of Example 4 Base] methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline- Add 33 mg (0.10 mmol) of cesium carbonate and 11 μl (0.094 mmol) of 1-iodo-2-methylpropane to a solution of 5-alcohol in 1 ml of tetrahydrofuran, stir the reaction solution at room temperature for 2 hours, and stir at 50 ° C for 3 hours, then in Stir at room temperature for 14 hours. After stirring at room temperature, 50 µl (0.43 mmol) of 1-iodo-2-methylpropane and 50 mg (0.15 mmol) of cesium carbonate were added, and the reaction solution was stirred at 70°C for 9 hours. After stirring under heating, 50 µl (0.43 mmol) of 1-iodo-2-methylpropane and 100 mg (0.31 mmol) of cesium carbonate were further added, and the reaction solution was stirred at room temperature for 14.5 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-70/30 (V/V)], and the fractions containing the desired compound were concentrated under reduced pressure. n-Hexane was added to the obtained residue, and a precipitate was obtained by filtration to obtain 41 mg of the title compound as a white solid (yield: 68%).

Specific rotation: [α] _D ²⁷ = -65° (C = 0.15, methanol).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δ: 8.01 (2H, s), 7.65 (2H, d, J = 8Hz), 7.38 (2H, d, J = 8Hz), 7.22 (1H, d, J=47Hz), 5.13(1H, dt, J=6, 6Hz), 4.71-4.59(1H, m), 4.41-4.30(1H, m), 3.70-3.57(1H, m), 3.67(2H, d , J=7Hz), 2.88-2.55(4H, m), 2.37-1.57(16H, m), 1.13(3H, s), 1.00(3H, s), 0.99(6H, d, J=7Hz), 0.66 -0.55(1H,m).

Mass Spectrum (EI, m/z): 704[M ⁺ ].

(Example 22)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1 -[5-(3-Methylbutoxy)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol

Except that 62 μl (0.47 mmol) of 1-iodo-3-methylbutane was used instead of 1-iodo-2-methylpropane and 55 mg (0.085 mmol) of (-)- 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piper Pyridin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol Reactions similar to those of Example 21, except starting, gave 40 mg as a white solid The title compound (yield: 65%).

Specific rotation: [α] _D ²⁷ = -69° (C = 0.18, methanol).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δ: 8.01 (2H, s), 7.65 (2H, d, J = 8Hz), 7.38 (2H, d, J = 8Hz), 7.22 (1H, d, J=48Hz), 5.13(1H, dt, J=6, 6Hz), 4.70-4.59(1H, m), 4.42-4.30(1H, m), 3.93(2H, t, J=7Hz), 3.72-3.56 (1H, m), 2.86-2.55 (4H, m), 2.37-1.56 (18H, m), 1.13 (3H, s), 1.00 (3H, s), 0.94 (6H, d, J=7Hz), 0.67 -0.57(1H, m).

Mass Spectrum (EI, m/z): 718[M ⁺ ].

(Example 23)

(-)-2-{1-[5-(4-carboxybutoxy)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluorocyclohexyl)-3-{ Fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

(23-1)

2-{1-[5-(4-ethoxycarbonylbutoxy)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluorocyclohexyl)-3-{fluoro Substituent[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

Except that ethyl 5-bromopentanoate was used instead of iodoethane and from 85 mg (0.13 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3 prepared by a method similar to that of Example 10 -{Fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl - 5,6,7,8-Tetrahydroquinolin-5-ol Starting with reactions analogous to those of Example 13, the crude title compound was obtained. The entire amount of the obtained compound was used in Example (23-2). (23-2)

(-)-2-{1-[5-(4-carboxybutoxy)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluorocyclohexyl)-3-{ Fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

To the crude product (-)-2-{1-[5-(4-ethoxycarbonylbutoxy)pyrimidin-2-yl]piperidin-4-yl}-4 obtained in Example (23-1) -(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetra Hydroquinolin-5-ol was added with 2 ml of tetrahydrofuran, 2 ml of ethanol and 1 ml (1.00 mmol) of 1N aqueous sodium hydroxide solution, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, 1N hydrochloric acid was poured into the reaction solution under ice-cooling, and the reaction solution was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by high performance liquid chromatography [YMC-pack ODS-A; 0.1% acetic acid and 0.1% triethylamine in acetonitrile/water solution = 85/15 (V/V)] to obtain 63 mg of The title compound (yield in two steps: 64%).

Specific rotation: [α] _D ²⁴ = -92° (C = 0.13, chloroform).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.01 (2H, s), 7.63 (2H, d, J = 8Hz), 7.35 (2H, d, J = 8Hz), 7.20 (1H, d, J = 48Hz), 5.12(1H, t, J=5Hz), 4.68-4.59(1H, m), 4.40-4.30(1H, m), 3.95-3.85(2H, m), 3.67-3.55(1H, m), 2.86-2.58(4H, m), 2.46-1.58(21H, m), 1.14(3H, s), 1.00(3H, s), 0.67-0.56(1H, m).

Mass spectrum (FAB, m/z): 749[(M+1) ⁺ ].

(Example 24)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1 -[5-(2-Methylpropyl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol

To 70 mg (0.085 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methanol prepared by a method similar to that of Reference Example 19 Base}-2-{1-[5-(1-hydroxy-2-methylpropyl)pyrimidin-2-yl]piperidin-4-yl}-5-[(4-methoxybenzyl)oxy base]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline in 5ml of dichloromethane solution was added 2ml of triethylsilane and 1ml of trifluoroacetic acid, the reaction solution was stirred at room temperature 41 Hour. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-85/15 (V/V)], and fractions containing the desired compound were concentrated under reduced pressure. n-Hexane was added to the obtained residue, and a precipitate was obtained by filtration to obtain 16 mg of the title compound as a white solid (yield: 27%).

Specific rotation: [α] _D ²⁴ = -88° (C = 0.050, methanol).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δ: 8.05 (2H, s), 7.65 (2H, d, J = 8Hz), 7.39 (2H, d, J = 8Hz), 7.22 (1H, d, J=47Hz), 5.13(1H, dt, J=6, 6Hz), 4.80-4.68(1H, m), 4.51-4.39(1H, m), 3.72-3.55(1H, m), 2.88-2.55(4H , m), 2.37-1.49 (18H, m), 1.13 (3H, s), 0.99 (3H, s), 0.88 (6H, d, J=7Hz), 0.68-0.57 (1H, m).

Mass Spectrum (EI, m/z): 688[M ⁺ ].

(Example 25)

(-)-2-{1-[5-(4-carboxybutyl)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluorocyclohexyl)-3-{fluoro Substituent[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

Reactions similar to those of the first step of Example 2, Example 38 and Example (23-2) were carried out, from 100 mg (0.148 mmol) of (-)- 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]- 7,7-Dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline to give 79 mg of the title compound as a white solid (yield: 73%). Instead of 5-bromo-2-chloropyrimidine corresponding to the first step of Example 2, methyl 5-(2-chloropyrimidin-5-yl)pentanoate was used, prepared by a method similar to that of Reference Example 20 .

Specific rotation: [α] _D ²⁵ = -68° (C = 0.14, chloroform).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.09 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.21 (1H, d, J = 47Hz), 5.15-5.08(1H, m), 4.78-4.68(1H, m), 4.50-4.40(1H, m), 3.67-3.57(1H, m), 2.84-2.59(4H, m), 2.47- 1.49(23H, m), 1.14(3H, s), 1.00(3H, s), 0.67-0.59(1H, m).

Mass spectrum (FAB, m/z): 733[(M+1) ⁺ ].

(Example 26)

(-)-4-(4,4-difluorocyclohexyl)-2-{1-[5-(ethoxymethyl)pyrimidin-2-yl]piperidin-4-yl}-3-{fluoro [4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

To 68 mg (0.085 mmol) of 4-(4,4-difluorocyclohexyl)-2-{1-[5-(ethoxymethyl)pyrimidine-2 prepared by a method similar to that of Reference Example 21 -yl]piperidin-4-yl}-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7, To a solution of 7-dimethyl-5,6,7,8-tetrahydroquinoline in 1 ml of dichloromethane was added 46 μl of anisole and 130 μl of trifluoroacetic acid, and the reaction solution was stirred at room temperature for 19 hours. Then, 100 µl of trifluoroacetic acid was further added, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=98/2-70/30 (V/V)], and fractions containing the desired compound were concentrated under reduced pressure. n-Hexane was added to the obtained residue, and a precipitate was obtained by filtration to obtain 34 mg of the title compound as a white solid (yield: 58%).

Specific rotation: [α] _D ²⁴ = -65° (C = 0.055, methanol).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δ: 8.20 (2H, s), 7.66 (2H, d, J = 8Hz), 7.39 (2H, d, J = 8Hz), 7.22 (1H, d, J=47Hz), 5.12(1H, dt, J=6, 6Hz), 4.84-4.74(1H, m), 4.55-4.44(1H, m), 4.25(2H, s), 3.71-3.56(1H, m ), 3.47(2H, q, J=7Hz), 2.91-2.55(4H, m), 2.36-1.55(15H, m), 1.17(3H, t, J=7Hz), 1.13(3H, s), 0.99 (3H, s), 0.68-0.58 (1H, m).

Mass Spectrum (EI, m/z): 690[M ⁺ ].

(Example 27)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(methoxy Methyl)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

Except using 42 mg (0.053 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl] prepared by a method similar to that of Reference Example 22 Methyl}-5-[(4-methoxybenzyl)oxy]-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}-7 , 7-Dimethyl-5,6,7,8-tetrahydroquinoline instead of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl] Methyl}-2-{1-[5-(1-hydroxy-2-methylpropyl)pyrimidin-2-yl]piperidin-4-yl}-5-[(4-methoxybenzyl) Except for oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, reactions similar to those of Example 24 were carried out to obtain 34 mg of the title compound as a foam (yield: 96% ).

Specific rotation: [α] _D ²⁴ = -82° (C = 0.090, methanol).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δ: 8.19 (2H, s), 7.66 (2H, d, J = 8Hz), 7.39 (2H, d, J = 8Hz), 7.23 (1H, d, J=47Hz), 5.13(1H, dt, J=6, 6Hz), 4.86-4.74(1H, m), 4.56-4.45(1H, m), 4.20(2H, s), 3.72-3.56(1H, m ), 3.30(3H, s), 2.90-2.55(4H, m), 2.37-1.48(15H, m), 1.13(3H, s), 0.99(3H, s), 0.68-0.58(1H, m).

Mass Spectrum (EI, m/z): 676[M ⁺ ].

(Example 28)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-(1 -{5-[(prop-2-yloxy)methyl]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinolin _- 5 _- ol

Except using 54 mg (0.065 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl] prepared by a method similar to that of Reference Example 23 Methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(1-{5-[(propan-2-yloxy)methyl]pyrimidine -2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinoline instead of 4-(4,4-difluorocyclohexyl)-2-{1-[5-(ethoxy Cylmethyl)pyrimidin-2-yl]piperidin-4-yl}-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl )oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, reactions similar to those of Example 26 afforded 31 mg of the title compound as a white solid (yield: 67%).

Specific rotation: [α] _D ²⁴ = -92° (C = 0.050, methanol).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δ: 8.19 (2H, s), 7.66 (2H, d, J = 8Hz), 7.39 (2H, d, J = 8Hz), 7.22 (1H, d, J=47Hz), 5.13(1H, dt, J=6, 6Hz), 4.83-4.72(1H, m), 4.56-4.43(1H, m), 4.25(2H, s), 3.72-3.56(1H, m ), 3.63(1H, dq, J=6, 6Hz), 2.92-2.54(4H, m), 2.38-1.44(15H, m), 1.15(6H, d, J=6Hz), 1.13(3H, s) , 0.99(3H, s), 0.67-0.57(1H, m).

Mass Spectrum (EI, m/z): 704[M ⁺ ].

(Example 29)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-(1 -{5-[(2-methylpropoxy)methyl]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinolin-5-ol

Except using 59 mg (0.070 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl] prepared by a method similar to that of Reference Example 24 Methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(1-{5-[(2-methylpropoxy)methyl]pyrimidine -2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinoline instead of 4-(4,4-difluorocyclohexyl)-2-{1-[5-(ethoxy Cylmethyl)pyrimidin-2-yl]piperidin-4-yl}-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl )oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, reactions similar to those of Example 26 afforded 35 mg of the title compound as a white solid (yield: 69%).

Specific rotation: [α] _D ²⁴ = -110° (C = 0.050, methanol).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δ: 8.20 (2H, s), 7.66 (2H, d, J = 8Hz), 7.39 (2H, d, J = 8Hz), 7.23 (1H, d, J=47Hz), 5.13(1H, dt, J=6, 6Hz), 4.84-4.74(1H, m), 4.56-4.45(1H, m), 4.25(2H, s), 3.71-3.57(1H, m ), 3.17(2H, d, J=7Hz), 2.89-2.55(4H, m), 2.36-1.56(16H, m), 1.13(3H, s), 0.99(3H, s), 0.88(6H, d , J=7Hz), 0.67-0.57(1H, m).

Mass Spectrum (EI, m/z): 718[M ⁺ ].

(Example 30)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1-[5- (Methylcarbamoyl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol

Reactions similar to those of Example 38 were carried out, and the entire amount of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl) Phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-{1-[5-(methylcarbamoyl)pyrimidine-2- yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinoline as a crude product to obtain 28 mg of the title compound as a white solid (yield: 54%).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.60 (2H, s), 7.64 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.22 (1H, d, J = 46Hz), 5.89(1H, brs), 5.15-5.08(1H, m), 4.92-4.84(1H, m), 4.65-4.56(1H, m), 3.69-3.59(1H, m), 2.97(3H, d, J=5Hz), 2.89-2.47(4H, m), 2.35-1.55(15H, m), 1.14(3H, s), 1.00(3H, s), 0.70-0.62(1H, m).

Mass Spectrum (ES, m/z): 690[M ⁺ ].

(Example 31)

(-)-4-(4,4-difluorocyclohexyl)-2-{1-[5-(dimethylcarbamoyl)pyrimidin-2-yl]piperidin-4-yl}-3-{ Fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

Except that aqueous dimethylamine was used instead of aqueous methylamine and 70 mg of the crude product 2-[1-(5-carboxypyrimidin-2-yl)piperidin-4-yl]- 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]- Starting from 7,7-dimethyl-5,6,7,8-tetrahydroquinoline, reactions similar to those of the second step of Reference Example 25 and Example 38 afforded 30 mg of The title compound (yield: 56%).

Specific rotation: [α] _D ²⁵ = -87° (C = 0.12, chloroform).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.40 (2H, s), 7.64 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.22 (1H, d, J = 47Hz), 5.15-5.09(1H, m), 4.91-4.82(1H, m), 4.62-4.55(1H, m), 3.67-3.59(1H, m), 3.08(6H, s), 2.93-2.60( 4H, m), 2.35-1.54 (15H, m), 1.14 (3H, s), 1.00 (3H, s), 0.69-0.62 (1H, m).

Mass Spectrum (ES, m/z): 704[M ⁺ ].

(Example 32)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1-[5- (Morpholin-4-yl-carbonyl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol

Except that morpholine was used instead of aqueous methylamine and 70 mg of the crude product 2-[1-(5-carboxypyrimidin-2-yl)piperidin-4-yl]-4- (4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7, Starting with 7-dimethyl-5,6,7,8-tetrahydroquinoline, reactions similar to those of the second step of Reference Example 25 and Example 38 afforded 27 mg of the title compound as a white solid (Yield: 49%).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.37 (2H, s), 7.64 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.22 (1H, d, J = 47Hz), 5.12(1H, q, J=6Hz), 4.90-4.82(1H, m), 4.63-4.54(1H, m), 3.78-3.54(9H, m), 2.90-2.59(4H, m), 2.36-1.56(15H, m), 1.14(3H, s), 1.00(3H, s), 0.70-0.61(1H, m).

Mass Spectrum (ES, m/z): 746[M ⁺ ].

(Example 33)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1-[5- (4,4,4-trifluorobutyl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol

Except using 2-chloro-5-(4,4,4-trifluorobutyl)pyrimidine prepared by a method similar to that of Reference Example 26 instead of 5-bromo-2-chloropyrimidine and from a method similar to that of Reference Example 70 mg (0.10 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}- 5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline started, Reactions similar to those of the first step of Example 2 and Example 38 were carried out to obtain 45 mg of the title compound as a white solid (yield: 61%).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.09 (2H, s), 7.64 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.21 (1H, d, J = 45Hz), 5.17-5.07(1H, m), 4.81-4.71(1H, m), 4.53-4.43(1H, m), 3.68-3.57(1H, m), 2.85-2.58(4H, m), 2.47( 2H, t, J=7Hz), 2.37-1.59(19H, m), 1.15(3H, s), 1.01(3H, s), 0.68-0.59(1H, m).

Mass spectrum (FAB, m/z): 743[(M+1) ⁺ ].

(Example 34)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-(1 -{5-[(1E)-3-Methylbut-1-en-1-yl]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinoline- 5-ol

To 118 mg (0.141 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methanol prepared by a method similar to that of Reference Example 27 Base}-2-{1-[5-(1-hydroxy-3-methylbutyl)pyrimidin-2-yl]piperidin-4-yl}-5-[(4-methoxybenzyl)oxy Add 2ml of 2N hydrochloric acid to a solution of -7,7-dimethyl-5,6,7,8-tetrahydroquinoline in 2ml of 1,4-dioxane, and stir the reaction solution at 100°C for 3.5 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=92/8-88/12 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 72 mg as white The title compound as a solid (yield: 73%).

Specific rotation: [α] _D ²⁴ = -89° (C = 0.15, methanol).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δ: 8.24 (2H, s), 7.66 (2H, d, J = 8Hz), 7.39 (2H, d, J = 8Hz), 7.23 (1H, d, J=47Hz), 6.11(1H, d, J=16Hz), 6.02(1H, dd, J=16, 6Hz), 5.13(1H, dt, J=6, 6Hz), 4.85-4.71(1H, m) , 4.56-4.41(1H, m), 3.73-3.56(1H, m), 2.89-2.54(4H, m), 2.49-1.55(16H, m), 1.13(3H, s), 1.06(6H, d, J=7Hz), 0.99(3H, s), 0.69-0.57(1H, m).

Mass Spectrum (EI, m/z): 700[M ⁺ ].

(Example 35)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1-[5- (3-Methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol

To 96 mg (0.12 mmol) of 2-[1-(5-carboxypyrimidin-2-yl)piperidin-4-yl]-4-(4 , 4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7- Dimethyl-5,6,7,8-tetrahydroquinoline was added with 3ml of acetonitrile, 2ml of tetrahydrofuran, 27mg (0.36mmol) of hydroxyacetamidine, 58mg (0.30mmol) of 1-ethyl-3-(3-dimethyl Aminopropyl) carbodiimide hydrochloride, 50 µl (0.36 mmol) of triethylamine and 41 mg (0.30 mmol) of 1-hydroxybenzotriazole, and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed successively with 0.1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.

The obtained crude product was dissolved in 2 ml of N,N-dimethylacetamide, and the reaction solution was stirred at 120° C. for 2 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=97/3-4/1 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 57 mg (0.068 mmol) 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy ]-7,7-dimethyl-2-{1-[5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl]piperidin-4-yl }-5,6,7,8-tetrahydroquinoline.

57 mg (0.068 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methyl) obtained from above Oxybenzyl)oxy]-7,7-dimethyl-2-{1-[5-(3-methyl-1,2,4-oxadiazol-5-yl)pyrimidin-2-yl ]piperidin-4-yl}-5,6,7,8-tetrahydroquinoline Reactions similar to those of Example 38 were carried out to obtain 35 mg of the title compound as a white solid (yield: 72%).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.87 (2H, s), 7.65 (2H, d, J = 8Hz), 7.38 (2H, d, J = 8Hz), 7.22 (1H, d, J = 47Hz), 5.16-5.08(1H, m), 4.99-4.90(1H, m), 4.73-4.63(1H, m), 3.69-3.57(1H, m), 2.90-2.58(4H, m), 2.43( 3H, s), 2.36-2.06 (6H, m), 1.98-1.58 (9H, m), 1.14 (3H, s), 1.00 (3H, s), 0.73-0.64 (1H, m).

Mass spectrum (FAB, m/z): 715[(M+1) ⁺ ].

(Example 36)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-(5-{[(2 -Hydroxyethyl)(methyl)amino]methyl}pyrimidin-2-yl)piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5 -alcohol

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-formylpyrimidin-2-yl) Piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

From 410 mg (0.525 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methanol prepared by a method similar to that of Reference Example 16 Base}-2-[1-(5-formylpyrimidin-2-yl)piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl -5,6,7,8-Tetrahydroquinoline started to react analogously to those of Example 38, affording 309 mg (0.468 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[ 4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-formylpyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6 , 7,8-tetrahydroquinolin-5-ol.

(36-2)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-(5-{[(2 -Hydroxyethyl)(methyl)amino]methyl}pyrimidin-2-yl)piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5 -alcohol

To 70 mg (0.11 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}- 2-[1-(5-formylpyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol at 1.0 6.1 μl (0.11 mmol) of acetic acid, 26 μl (0.32 mmol) of 2-(methylamino)ethanol and 68 mg (0.32 mmol) of sodium triacetoxyborohydride were added to a solution in ml tetrahydrofuran, and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the reaction solution was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [dichloromethane/methanol/28% aqueous ammonia solution=95/4.75/0.25-80/19/1 (V/V/V)] to obtain 68 mg of the title as a white solid Compound (Yield: 89%).

Specific rotation: [α] _D ²⁵ = -80° (C = 0.11, chloroform).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.15 (2H, s), 7.64 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.21 (1H, d, J = 49Hz), 5.16-5.09(1H, m), 4.83-4.74(1H, m), 4.55-4.47(1H, m), 3.68-3.57(3H, m), 3.38(2H, s), 2.94-2.60( 5H, m), 2.57(2H, t, J=5Hz), 2.37-1.56(15H, m), 2.20(3H, s), 1.14(3H, s), 1.00(3H, s), 0.68-0.61( 1H, m).

Mass Spectrum (ES, m/z): 720[M ⁺ ].

(Example 37)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-{[(2S )-2-hydroxypropyl]oxy}pyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

Except the 4-toluenesulfonic acid (2S)-2-(tetrahydro-2H-pyran-2 -yloxy)propyl ester instead of iodoethane and from 50 mg (77 μmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluorocyclohexyl)-3-{fluoro Substitute [4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5, 6,7,8-Tetrahydroquinolin-5-ol started with reactions analogous to those of Example 13 to give 49 mg (62 μmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro Substituting [4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-[1-(5-{[(2S)-2-(tetrahydro-2H-pyran- 2-yloxy)propyl]oxy}pyrimidin-2-yl)piperidin-4-yl]-5,6,7,8-tetrahydroquinolin-5-ol.

To 49 mg (62 μmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl- 2-{1-(5-{[(2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl]oxy}pyrimidin-2-yl)piperidin-4-yl} - To a solution of 5,6,7,8-tetrahydroquinolin-5-ol in 1.0 ml of methanol was added 0.1 mg (0.6 μmol) of p-toluenesulfonic acid monohydrate, and the reaction solution was stirred at 60° C. for 2 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added to the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=9/1-3/2 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 41 mg as white The title compound as a solid (yield: 93%).

Specific rotation: [α] _D ²⁴ = -64° (C = 0.24, chloroform).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.04 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.21 (1H, d, J = 47Hz), 5.12(1H, q, J=6Hz), 4.71-4.63(1H, m), 4.42-4.35(1H, m), 4.18-4.10(1H, m), 3.86(1H, dd, J=3 , 9Hz), 3.73 (1H, dd, J=8, 9Hz), 3.67-3.58 (1H, m), 2.91-2.62 (4H, m), 2.37-1.59 (16H, m), 1.25 (3H, d, J=6Hz), 1.14(3H, s), 1.00(3H, s), 0.67-0.59(1H, m).

Mass Spectrum (ES, m/z): 707[M ⁺ ].

(Example 38)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-(1-{5- [(1-Methylpiperidin-4-yl)oxy]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinolin-5-ol

To 86 mg (99 μmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl) prepared by a method similar to that of Reference Example 29 }-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(1-{5-[(1-methylpiperidin-4-yl)oxy] A solution of pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinoline in 1.0ml of dichloromethane was added with 0.2ml of anisole and 0.2ml of trifluoroacetic acid at room temperature The reaction solution was stirred for 12 hours. After the reaction was completed, the solvent of the reaction solution and trifluoroacetic acid were distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [dichloromethane/methanol/28% ammonia water=100/0/0-90/9.5/0.5 (V/V/V)] and thin layer chromatography [dichloromethane Methane/methanol/28% ammonia water=90/9.5/0.5 (V/V/V)] purification to obtain 12 mg of the title compound as a white solid (yield: 17%).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.03 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.21 (1H, d, J = 46Hz), 5.17-5.06(1H, m), 4.73-4.62(1H, m), 4.45-4.34(1H, m), 4.06-3.92(1H, m), 3.70-3.56(1H, m), 2.88- 2.57(6H, m), 2.38-1.53(21H, m), 2.28(3H, s), 1.15(3H, s), 1.01(3H, s), 0.69-0.59(1H, m).

Mass spectrum (FAB, m/z): 746[(M+1) ⁺ ].

(Example 39)

(-)-4-(4,4-difluorocyclohexyl)-2-[1-(5-{[(2S)-2,3-dihydroxypropyl]oxy}pyrimidin-2-yl)piper Pyridin-4-yl]-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5 -alcohol

To 389 mg (0.600 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)benzene prepared by a method similar to that of Example 4 Base] methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline- A solution of 5-alcohol in 3 ml of 1-methyl-2-pyrrolidone was added with 489 mg (1.50 mmol) cesium carbonate and 344 mg (1.20 mmol) p-toluenesulfonic acid (S)-(+)-2,2-dimethyl-1 , 3-dioxolan-4-ylmethyl ester, the reaction solution was stirred at 70°C for 2 hours. After the reaction was completed, water and ethyl acetate were poured into the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-50/50 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain a white solid 400mg (0.524mmol) of 4-(4,4-difluorocyclohexyl)-2-[1-(5-{[(4R)-2,2-dimethyl-1,3-dioxolane- 4-yl]methoxy}pyrimidin-2-yl)piperidin-4-yl]-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl -5,6,7,8-tetrahydroquinolin-5-ol.

400 mg (0.524 mmol) of 4-(4,4-difluorocyclohexyl)-2-[1-(5-{[(4R)-2,2-dimethyl-1,3-dioxo Pentyl-4-yl]methoxy}pyrimidin-2-yl)piperidin-4-yl]-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7- Dimethyl-5,6,7,8-tetrahydroquinolin-5-ol was added with 5.2 ml of methanol and 1.3 ml of 2N hydrochloric acid, and the reaction solution was stirred at 60°C for 2 hours. After the reaction was completed, 1.3 ml of 2N aqueous sodium hydroxide solution, saturated aqueous sodium chloride solution and ethyl acetate were poured into the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. n-Hexane was added to the obtained residue, and a precipitate was obtained by filtration to obtain 307 mg of the title compound as a white solid (yield: 71%).

Specific rotation: [α] _D ²⁷ = -72° (C = 0.12, methanol).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δ: 8.05 (2H, s), 7.65 (2H, d, J = 8Hz), 7.38 (2H, d, J = 8Hz), 7.22 (1H, d, J=47Hz), 5.13(1H, dt, J=6, 6Hz), 4.72-4.60(1H, m), 4.43-4.31(1H, m), 4.07-3.90(3H, m), 3.76(1H, ddd , J = 11, 6, 4Hz), 3.67 (1H, dt, J = 11, 5Hz), 3.64-3.57 (1H, m), 2.85-2.56 (4H, m), 2.51 (1H, d, J = 5Hz ), 2.36-1.58(16H, m), 1.13(3H, s), 1.00(3H, s), 0.67-0.57(1H, m).

Mass Spectrum (EI, m/z): 722[M ⁺ ].

(Example 40)

(-)-4-(4,4-difluorocyclohexyl)-2-[1-(5-{[(2R)-2,3-dihydroxypropyl]oxy}pyrimidin-2-yl)piper Pyridin-4-yl]-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5 -alcohol

In addition to using p-toluenesulfonic acid (R)-(-)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl ester instead of p-toluenesulfonic acid (S)-(+)-2 , 2-Dimethyl-1,3-dioxolan-4-ylmethyl ester, reactions similar to those of Example 39 were carried out to obtain 252 mg of the title compound as a white solid (yield: 58%).

Specific rotation: [α] _D ²⁷ = -102° (C = 0.14, methanol).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δ: 8.05 (2H, s), 7.65 (2H, d, J = 8Hz), 7.39 (2H, d, J = 8Hz), 7.22 (1H, d, J=47Hz), 5.13(1H, dt, J=6, 6Hz), 4.72-4.60(1H, m), 4.43-4.31(1H, m), 4.07-3.90(3H, m), 3.76(1H, ddd , J=11, 6, 4Hz), 3.67(1H, dt, J=11, 6Hz), 3.64-3.57(1H, m), 2.86-2.56(4H, m), 2.52(1H, dt, J=4Hz ), 2.35-1.57(16H, m), 1.13(3H, s), 1.00(3H, s), 0.68-0.56(1H, m).

Mass Spectrum (EI, m/z): 722[M ⁺ ].

(Example 41)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-[1-(5- {[(3R)-1-Methylpyrrolidin-3-yl]oxy}pyrimidin-2-yl)piperidin-4-yl]-5,6,7,8-tetrahydroquinolin-5-ol

Except that 2-chloro-5-{[(3R)-1-methylpyrrolidin-3-yl]oxy}pyrimidine prepared by a method similar to that of Reference Example 30 was used instead of 2-chloro-5-[ (1-methylpiperidin-4-yl)oxy]pyrimidine and 100 mg (0.155 mmol) of (-)-4-(4,4-difluorocyclohexyl) prepared by a method similar to that of Reference Example 10 )-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-( Starting with piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, reactions similar to those of Reference Example 29 and Example 38 afforded 58 mg of the title compound as a white solid (yield: 44%).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 7.99 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.21 (1H, d, J = 48Hz), 5.16-5.06(1H, m), 4.72-4.57(2H, m), 4.43-4.31(1H, m), 3.70-3.55(1H, m), 2.90-2.57(6H, m), 2.47- 1.57(19H, m), 2, 38(3H, s), 1.15(3H, s), 1.00(3H, s), 0.70-0.58(1H, m).

Mass spectrum (FAB, m/z): 732[(M+1) ⁺ ].

(Example 42)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-{[(2R )-2-hydroxypropyl]oxy}pyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

Except for 4-methylbenzenesulfonic acid (2R)-2-(tetrahydro-2H-pyran-2 synthesized by the method described in B.A.Jones et al., Journal of Heterocyclic Chemistry, 1982, Volume 19, pages 551-556 (2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl ester instead of (2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl ester and from a method similar to that of Example 4 Prepared 50 mg (77 μmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidine Starting with -2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, reactions analogous to those of Example 37 were carried out, 39 mg of the title compound were obtained as a white solid (yield: 71%).

Specific rotation: [α] _D ²⁴ = -80° (C = 0.14, chloroform).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.04 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.21 (1H, d, J = 47Hz), 5.12(1H, qJ=6Hz), 4.71-4.62(1H, m), 4.43-4.34(1H, m), 4.19-4.11(1H, m), 3.87(1H, dd, J=3, 9Hz ), 3.73 (1H, dd, J=8, 9Hz), 3.67-3.57 (1H, m), 2.93-2.60 (4H, m), 2.40-1.56 (16H, m), 1.25 (3H, d, J= 6Hz), 1.14(3H, s), 1.00(3H, s), 0.67-0.59(1H, m).

Mass Spectrum (ES, m/z): 707[M ⁺ ].

(Example 43)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(3-hydroxy -3-methylbutoxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

To 300 mg (0.462 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)benzene prepared by a method similar to that of Example 4 Base] methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline- A solution of 5-alcohol in 2.3 ml of N,N-dimethylformamide was added with 301 mg (0.924 mmol) of cesium carbonate and synthesized using the method described in Yagamare Fall et al., Tetrahedron Letters, 2000, Vol. 41, pp. 7337-7340 93mg (0.55mmol) of 4-bromo-2-methylbutan-2-ol, and the reaction solution was stirred at 50°C for 1 hour. After the reaction was completed, water was poured into the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=70/30-50/50 (V/V)], and the fractions containing the desired compound were concentrated under reduced pressure. n-Hexane was added to the obtained residue, and a precipitate was obtained by filtration to obtain 161 mg of the title compound as a white powder (yield: 47%).

Specific rotation: [α] _D ²⁰ = -72.2° (C = 1.03, chloroform).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δ: 8.04 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.20 (1H, d, J = 46Hz), 5.12(1H, dt, J=6, 6Hz), 4.74-4.61(1H, m), 4.46-4.33(1H, m), 4.11(2H, t, J=6Hz), 3.70-3.54(1H , m), 2.91-2.58 (4H, m), 2.40-1.62 (18H, m), 1.30 (6H, s), 1.15 (3H, s), 1.00 (3H, s), 0.68-0.58 (1H, m ).

Mass Spectrum (EI, m/z): 734[M ⁺ ].

(Example 44)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(2-hydroxy-2-methyl Propyloxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

Except that ethyl bromoacetate was used instead of ethyl iodide and from 82 mg (0.13 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro Substitute [4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5, 6,7,8-Tetrahydroquinolin-5-ol started with reactions similar to those of Example 13 to give 61 mg of 4-(4,4-difluorocyclohexyl)-2-{1-[5- (2-ethoxy-2-oxoethoxy)pyrimidin-2-yl]piperidin-4-yl}-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7 , 7-Dimethyl-5,6,7,8-tetrahydroquinolin-5-ol. At 0°C, to 61 mg (0.083 mmol) of 4-(4,4-difluorocyclohexyl)-2-{1-[5-(2-ethoxy-2-oxoethoxy) obtained above Pyrimidin-2-yl]piperidin-4-yl}-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8 To a solution of -tetrahydroquinolin-5-ol in 5 ml of diethyl ether was added 0.30 ml (0.33 mmol) of 1.1N methylmagnesium bromide-diethyl ether solution. The temperature of the reaction solution was raised to room temperature and the reaction solution was stirred for 1 hour. After the reaction was completed, an aqueous ammonium chloride solution was poured into the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by thin-layer silica gel chromatography [n-hexane/ethyl acetate=5/6 (V/V)] to obtain 18 mg of the title compound as a white solid (yield: 30%).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.05 (2H, s), 7.63 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.21 (1H, d, J = 47Hz), 5.16-5.08(1H, m), 4.71-4.63(1H, m), 4.43-4.34(1H, m), 3.73(2H, s), 3.68-3.56(1H, m), 2.84-2.59( 4H, m), 2.37-1.47 (16H, m), 1.32 (6H, s), 1.15 (3H, s), 1.01 (3H, s), 0.67-0.58 (1H, m).

Mass spectrum (FAB, m/z): 721[(M+1) ⁺ ].

(Example 45)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-(1 -{5-[3-(methylsulfonyl)propoxy]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinolin-5-ol

In addition to using 3-(methylsulfonyl)propyl p-toluenesulfonate synthesized by the method described in the specification of U.S. Patent No. 6,593,333 instead of 4-bromo-2-methylbutan-2-ol and using 1-methyl- Reactions similar to those of Example 43 were carried out except that 2-pyrrolidone was used instead of N,N-dimethylformamide to obtain 266 mg of the title compound as a white solid (yield: 44%).

Specific rotation: [α] _D ²⁷ = -74° (C = 0.16, chloroform).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δ: 8.03 (2H, s), 7.65 (2H, d, J = 8Hz), 7.39 (2H, d, J = 8Hz), 7.22 (1H, d, J=47Hz), 5.13(1H, dt, J=6, 6Hz), 4.71-4.60(1H, m), 4.43-4.31(1H, m), 4.04(2H, t, J=6Hz), 3.72-3.56 (1H, m), 3.20 (2H, dd, J=9, 7Hz), 2.91 (3H, s), 2.85-2.55 (4H, m), 2.35-1.57 (17H, m), 1.13 (3H, s) , 1.00(3H, s), 0.68-0.56(1H, m).

Mass Spectrum (EI, m/z): 768[M ⁺ ].

(Example 46)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(3-hydroxy Propoxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

Except that (3-bromopropoxy)(tert-butyl)dimethylsilane was used instead of iodoethane and from 61 mg (94 μmol) of (-)-4-(4 prepared by a method similar to that of Example 4, 4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl ]-7,7-Dimethyl-5,6,7,8-tetrahydroquinolin-5-ol starting with reactions similar to those of Example 13 afforded 71 mg (87 μmol) of 2-{1- [5-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluoro Cyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol.

To the 71 mg (87 μmol) of 2-{1-[5-(3-{[tert-butyl(dimethyl)silyl]oxy}propoxy)pyrimidin-2-yl]piperidine-4 obtained above -Base}-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6, To a solution of 7,8-tetrahydroquinolin-5-ol in 1 ml of tetrahydrofuran was added 0.5 ml (0.5 mmol) of 1N tetrabutylammonium fluoride-tetrahydrofuran solution, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=3/1 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 59 mg of the title compound as a white solid (Yield: 88%).

Specific rotation: [α] _D ²⁴ = -74° (C = 0.15, chloroform).

¹ H-NMR spectrum 400MHz, CDCl ₃ ) δppm: 8.03 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.21 (1H, d, J = 48Hz ), 5.16-5.07(1H, m), 4.72-4.62(1H, m), 4.43-4.33(1H, m), 4.05(2H, t, J=6Hz), 3.84(2H, t, J=6Hz) , 3.68-3.55(1H, m), 2.93-2.57(4H, m), 2.38-1.57(18H, m), 1.14(3H, s), 1.00(3H, s), 0.67-0.58(1H, m) .

Mass spectrum (FAB, m/z): 707[(M+1) ⁺ ].

(Example 47)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1 -[5-(3,3,3-trifluoropropoxy)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol

Except using 2-chloro-5-(3,3,3-trifluoropropoxy)pyrimidine prepared by a method similar to that of Reference Example 31 instead of 2-chloro-5-[(1-methylpiperidine -4-yl)oxy]pyrimidine and 150 mg (222 μmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[ 4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)- Except starting with 5,6,7,8-tetrahydroquinoline, reactions similar to those of Reference Example 29 and Example 38 were carried out to obtain 85 mg of the title compound as a white solid (yield: 51%).

Specific rotation: [α] _D ²⁵ = -69° (C = 0.20, chloroform).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.03 (2H, s), 7.63 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.21 (1H, d, J = 46Hz), 5.17-5.07(1H, m), 4.73-4.66(1H, m), 4.45-4.34(1H, m), 4.18-4.06(2H, m), 3.69-3.56(1H, m), 2.86- 2.48(6H, m), 2.30-1.54(15H, m), 1.15(3H, s), 1.01(3H, s), 0.69-0.58(1H, m).

Mass spectrum (FAB, m/z): 745[(M+1) ⁺ ].

(Example 48)

(-)-4-(4,4-difluorocyclohexyl)-2-{1-[5-(difluoromethoxy)pyrimidin-2-yl]piperidin-4-yl}-3-{fluoro Substituent[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

Except that 2-chloro-5-[(1-methylpiperidin-4-yl)oxy Base]pyrimidine and 102 mg (151 μmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl) prepared by a method similar to that of Reference Example 10 Base) phenyl] methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7, Except starting with 8-tetrahydroquinoline, reactions similar to those of Reference Example 29 and Example 38 were performed to obtain 52 mg of the title compound as a white solid (yield: 49%).

Specific rotation: [α] _D ²⁵ = -77° (C = 0.15, chloroform).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.12 (2H, s), 7.64 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7, 21 (1H, d, J=47Hz), 6.36(1H, t, J=73Hz), 5.16-5.08(1H, m), 4.80-4.70(1H, m), 4.52-4.43(1H, m), 3.68-3.57(1H, m ), 2.86-2.59(4H, m), 2.35-1.54(15H, m), 1.15(3H, s), 1.01(3H, s), 0.69-0.60(1H, m).

Mass spectrum (FAB, m/z): 699[(M+1) ⁺ ].

(Example 49)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5-[3-hydroxyl -2-(Hydroxymethyl)propoxy]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

Except adopting p-toluenesulfonic acid (2,2-dimethyl-1,3-dioxane-5 -yl) methyl ester instead of (S)-(+)-2,2-dimethyl-1,3-dioxolan-4-yl methyl ester and obtained from a method similar to Example 4 4.04 g (6.23 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2 prepared by method -[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol started, carried out Reactions similar to those of Example 39 gave 2.73 g of the title compound as a white solid (yield: 59%).

Specific rotation: [α] _D ²⁸ = -91° (C = 0.21, methanol).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δ: 8.04 (2H, s), 7.65 (2H, d, J = 8Hz), 7.38 (2H, d, J = 8Hz), 7.22 (1H, d, J=47Hz), 5.13(1H, dt, J=6, 6Hz), 4.71-4.59(1H, m), 4.42-4.32(1H, m), 4.03(2H, d, J=6Hz), 3.91-3.78 (4H, m), 3.71-3.57 (1H, m), 2.86-2.55 (4H, m), 2.36-1.58 (18H, m), 1.13 (3H, s), 1.00 (3H, s), 0.68-0.57 (1H, m).

Mass Spectrum (EI, m/z): 736[M ⁺ ].

(Example 50)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5-[3-hydroxyl -2-(Hydroxymethyl)-2-methylpropoxy]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinone Lin-5-ol

To 182 mg (0.200 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methanol prepared by a method similar to that of Reference Example 34 Base}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(1-{5-[(2,2,5-trimethyl-1,3 -dioxan-5-yl)methoxy]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinoline in 9.1ml 1,4-dioxo To the solution in heterocyclohexane was added 0.91 ml of 6N hydrochloric acid, and the reaction solution was stirred at 70°C for 1 hour. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=20/30 (V/V)], and to the fraction containing the desired compound was added 50 mg (0.055 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxy benzyl)oxy]-7,7-dimethyl-2-(1-{5-[(2,2,5-trimethyl-1,3-dioxan-5-yl )methoxy]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinoline Starting from a reaction similar to the above, 30 mg of a white solid was obtained, and the mixture was concentrated under reduced pressure. n-Hexane was added to the obtained residue, and a precipitate was obtained by filtration to obtain 133 mg of the title compound as a white powder (yield: 69%).

Specific rotation: [α] _D ²⁷ = -60.8° (C = 0.530, chloroform).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δ: 8.04 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.20 (1H, d, J = 46Hz), 5.12(1H, dt, J=6, 6Hz), 4.72-4.60(1H, m), 4.45-4.32(1H, m), 3.92(2H, s), 3.77(2H, dd, J=11 , 5Hz), 3.70(2H, dd, J=11, 5Hz), 3.66-3.54(1H, m), 2.89-2.58(4H, m), 2.38-1.57(17H, m), 1.15(3H, s) , 1.00(3H, s), 0.94(3H, s), 0.68-0.57(1H, m).

Mass Spectrum (EI, m/z): 750[M ⁺ ].

(Example 51)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-[1 -(5-{[methyl(methylsulfonyl)amino]methyl}pyrimidin-2-yl)piperidin-4-yl]-5,6,7,8-tetrahydroquinolin-5-ol

To 65 mg (95 μmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl} prepared by a method similar to that of Example 58 -7,7-Dimethyl-2-(1-{5-[(methylamino)methyl]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydro A solution of quinolin-5-ol in 0.2 ml of dichloromethane was added with 30 µl (0.19 mmol) of triethylamine and 8 µl (0.1 mmol) of methanesulfonyl chloride, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, a saturated aqueous sodium bicarbonate solution was poured into the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=100/0-40/60 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 37 mg as white The title compound as a solid (Yield: 52%).

Specific rotation: [α] _D ²⁵ = -76° (C = 0.16, chloroform).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.22 (2H, s), 7.64 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.22 (1H, d, J = 48Hz), 5.16-5.07(1H, m), 4.85-4.76(1H, m), 4.59-4.47(1H, m), 4.11(2H, s), 3.70-3.54(1H, m), 2.88-2.71( 3H, m), 2.82 (3H, s), 2.75 (3H, s), 2.63 (1H, d, J=17Hz), 2.37-2.21 (2H, m), 2.21-2.07 (4H, m), 1.98- 1.52(9H, m), 1.14(3H, s), 1.00(3H, s), 0.72-0.61(1H, m).

Mass spectrum (FAB, m/z): 754[(M+1) ⁺ ].

(Example 52)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-[1-(5- {[Methyl(prop-2-ylsulfonyl)amino]methyl}pyrimidin-2-yl)piperidin-4-yl]-5,6,7,8-tetrahydroquinolin-5-ol

Except that isopropylsulfonyl chloride was used instead of methanesulfonyl chloride and from 64 mg (94 μmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4- (Trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-(1-{5-[(methylamino)methyl]pyrimidin-2-yl}piperidin-4-yl )-5,6,7,8-tetrahydroquinolin-5-ol, reactions similar to those of Example 51 were carried out to obtain 14 mg of the title compound as a white solid (yield: 19%).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.23 (2H, s), 7.64 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.21 (1H, d, J = 45Hz), 5.21-5.06(1H, m), 4.85-4.76(1H, m), 4.59-4.47(1H, m), 4.18(2H, s), 3.71-3.55(1H, m), 3.24(1H, Septet, J=7Hz), 2.87-2.70(3H, m), 2.77(3H, s), 2.63(1H, d, J=17Hz), 2.42-1.56(15H, m), 1.37(6H, d, J=7Hz), 1.14(3H, s), 1.00(3H, s), 0.71-0.59(1H, m).

Mass spectrum (FAB, m/z): 782[(M+1) ⁺ ].

(Example 53)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-[1 -(5-methylthiopyrimidin-2-yl)-piperidin-4-yl]-5,6,7,8-tetrahydroquinolin-5-ol

Except that 2-chloro-5-methylthiopyrimidine prepared by a method similar to that of Reference Example 36 was used instead of 5-bromo-2-chloropyrimidine and 60 mg of ( 89 μmol) (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl Base) oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, proceed similarly to Example 2 and Example 38 Reaction of those of the first step afforded 50 mg of the title compound as a white solid (yield: 84%).

Specific rotation: [α] _D ²⁶ = -89° (C = 0.17, chloroform).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.31 (2H, s), 7.64 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.21 (1H, d, J = 47Hz), 5.15-5.09(1H, m), 4.83-4.74(1H, m), 4.57-4.47(1H, m), 3.68-3.57(1H, m), 2.94-2.59(4H, m), 2.42- 1.47(15H, m), 2.32(3H, s), 1.14(3H, s), 1.00(3H, s), 0.69-0.60(1H, m).

Mass Spectrum (ES, m/z): 679[M ⁺ ].

(Example 54)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-{1 -[5-(methylsulfonyl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinolin-5-ol

Except using 2-chloro-5-(methylsulfonyl)pyrimidine prepared by a method similar to that of Reference Example 14 instead of 5-bromo-2-chloropyrimidine and prepared from a method similar to that of Reference Example 10 49 mg (72 μmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methyl Oxybenzyl) oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline started, carried out similarly to Example 2 and Reaction of those of the first step of Example 38 gave 45 mg of the title compound as a white solid (yield: 88%).

Specific rotation: [α] _D ²⁶ = -88° (C = 0.16, chloroform).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.62 (2H, s), 7.65 (2H, d, J = 8Hz), 7.38 (2H, d, J = 8Hz), 7.22 (1H, d, J = 47Hz), 5.13(1H, q, J=6Hz), 4.98-4.89(1H, m), 4.72-4.63(1H, m), 3.69-3.58(1H, m), 3.04(3H, s), 2.93- 2.59(4H, m), 2.36-1.55(15H, m), 1.14(3H, s), 1.00(3H, s), 0.75-0.65(1H, m).

Mass Spectrum (ES, m/z): 711[M ⁺ ].

(Example 55)

(-)-2-{1-[5-(3-carboxyphenyl)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluorocyclohexyl)-3-{fluoro Substituent[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

To 303 mg (0.450 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)benzene prepared by a method similar to that of Reference Example 10 Base] methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetra A solution of hydroquinoline in 3 ml of 1,4-dioxane was added to 127 mg (0.495 mmol) of 2-chloro-5-[3-(methoxycarbonyl) prepared by a method similar to that of Reference Example 35 ) phenyl]pyrimidine and 115 μl (0.675 mmol) of diisopropylethylamine, the reaction solution was stirred at 60°C for 1.5 hours, at 70°C for 4 hours, and then at 80°C for 1.5 hours. After stirring under heating, 35 μl (0.23 mmol) of 1,8-diazabicyclo[5,4,0]-7-undecene was added, and the reaction solution was stirred at 80°C for 1 hour and at 90°C for 1.5 hours, Then it was stirred at 100°C for 1 hour. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=90/10-50/50 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain a white solid 351mg of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy] -2-(1-{5-[3-(Methoxycarbonyl)phenyl]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8 - Tetrahydroquinoline.

351 mg of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl) obtained above Oxygen]-2-(1-{5-[3-(methoxycarbonyl)phenyl]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6, 2 ml of dichloromethane, 0.24 ml of anisole and 1 ml of trifluoroacetic acid were added to 7,8-tetrahydroquinoline, and the reaction solution was stirred at room temperature for 12.5 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-50/50 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain a white solid 257mg of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5-[3-(methoxy carbonyl)phenyl]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol.

To the 257mg 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5-[3-( Methoxycarbonyl)phenyl]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol was added to 2ml tetrahydrofuran, 3 ml of ethanol and 1 ml of 2N aqueous sodium hydroxide solution were stirred at room temperature for 3.5 hours. After the reaction was completed, 1 ml of 2N hydrochloric acid was added to the reaction solution. After stirring at room temperature, a saturated aqueous sodium chloride solution and ethyl acetate were poured into the reaction solution, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. To the obtained residue was added n-heptane, and a precipitate was obtained by filtration to obtain 240 mg of the title compound as a white solid (yield: 71%).

Specific rotation: [α] _D ²⁸ = -67.8° (C = 0.520, chloroform).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δ: 8.44 (2H, s), 8.07 (1H, s), 7.98 (1H, d, J=7Hz), 7.66 (2H, d, J=8Hz), 7.47 (1H, d, J = 7Hz), 7.46 (1H, t, J = 7Hz), 7.39 (2H, d, J = 8Hz), 7.24 (1H, d, J = 47Hz), 5.13 (1H, t, J =6Hz), 4.93-4.81(1H, m), 4.65-4.52(1H, m), 3.72-3.56(1H, m), 3.01-2.61(4H, m), 2.41-1.61(15H, m), 1.13 (3H, s), 0.99 (3H, s), 0.72-0.58 (1H, m).

Mass spectrum (EI, m/z): 752[M ⁺ ].

(Example 56)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5-[(2-hydroxyethyl) (Methyl)amino]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin _- 5 _- ol

Except that 2-(methylamino)ethanol was used instead of ethyl isopiperidine and 100 mg (0.120 mmol) of 2-[1-(5-bromopyrimidine-2- Base) piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4- Starting with methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, reactions similar to those of Reference Example 13 afforded 25 mg of 4-(4 , 4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5-[(2-hydroxyethyl)(methyl) Amino]pyrimidin-2-yl}piperidin-4-yl)-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydro Quinoline (yield: 26%).

To 25 mg (30 μmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5- [(2-Hydroxyethyl)(methyl)amino]pyrimidin-2-yl}piperidin-4-yl)-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl Add 0.1ml pyridine, 15μl (0.16mmol) acetic anhydride and 0.4mg (3μmol) 4-dimethylaminopyridine to a solution of base-5,6,7,8-tetrahydroquinoline in 1.0ml dichloromethane, The reaction solution was stirred at room temperature for 10 minutes. After the reaction was completed, water was added to the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.

The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=3/1-1/1 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain a white solid 25mg of 2-(1-{5-[(2-acetoxyethyl)(methyl)amino]pyrimidin-2-yl}piperidin-4-yl)-4-(4,4-difluorocyclohexyl) -3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6, 7,8-tetrahydroquinoline (yield: 93%).

Reactions similar to those of Example 38 and Example (23-2) were carried out, from 25 mg (29 μmol) of 2-(1-{5-[(2-acetoxyethyl)(methyl)amino] obtained above Pyrimidin-2-yl}piperidin-4-yl)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5- [(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline to give 13 mg of the title compound as a white solid (yield: 65%) . An aqueous potassium carbonate solution was used instead of the 1N aqueous sodium hydroxide solution in the step corresponding to Example (23-2).

¹ H _- NMR spectrum (500MHz, CD ₃ OD) δppm: 8.02 (2H, s), 7.73 (2H, d, J = 8Hz), 7.46 (2H, d, J = 8Hz), 7.28 (1H, d, J =47Hz), 5.20-5.12(1H, m), 4.60-5.50(1H, m), 4.28-4.18(1H, m), 3.77-3.63(3H, m), 3.36-3.23(2H, m), 2.95 -2.56(4H,m), 2.87(3H,s), 2.36-1.53(14H,m), 1.13(3H,s), 0.97(3H,s), 0.64-0.55(1H,m).

Mass Spectrum (ES, m/z): 706[M ⁺ ].

(Example 57)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-(1-{5-[(3S) -3-hydroxypyrrolidin-1-yl]pyrimidin-2-yl}piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol

Except that (3S)-3-pyrrolidinol was used instead of ethyl isopiperidine and 100 mg (0.120 mmol) of (-)-2-[1-(5- Bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5 -[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline Started with reactions similar to those of Reference Example 13 , to obtain 56 mg of the title compound as a white solid (yield: 65%).

Specific rotation: [α] _D ²⁶ = -63° (C = 0.13, chloroform).

¹ H-NMR spectrum (500MHz, DMSO-D ₆ ) δppm: 7.84 (2H, d, J=8Hz), 7.83 (2H, s), 7.42 (2H, d, J=8Hz), 7.19 (1H, d, J=46Hz), 5.19-5.11 (1H, m), 5.09-5.00 (1H, m), 4.93-4.90 (1H, m), 4.56-4.48 (1H, m), 4.39-4.34 (1H, m), 4.23-4.16(1H, m), 3.75-3.67(1H, m), 3.39-3.14(4H, m), 3.00-2.95(1H, m), 2.77-2.46(4H, m), 2.24-1.39(15H , m), 1.06(3H, s), 0.90(3H, s), 0.44-0.38(1H, m).

(Example 58)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-(1-{5- [(Methylamino)methyl]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinolin-5-ol

To 165 mg (0.250 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)benzene prepared by a method similar to that of Example (36-1) Base] methyl}-2-[1-(5-formylpyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline 1.0 ml of methanol, 0.1 ml of tetrahydrofuran and 0.20 ml (about 2.5 mmol) of about 40% methylamine-methanol solution were added to -5-ol, and the reaction solution was stirred at room temperature for 12 hours. Then, 95 mg (2.5 mmol) of sodium borohydride was added thereto, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, a saturated aqueous ammonium chloride solution was poured into the reaction solution until the bubbles disappeared. A saturated aqueous sodium bicarbonate solution was poured into the reaction solution to make the reaction solution basic and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [dichloromethane/methanol/28% aqueous ammonia=100/0/0-90/9.5/0.5 (V/V/V)] and concentrated under reduced pressure containing the desired 128 mg of the title compound was obtained as a colorless oil (yield: 76%).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.23 (2H, s), 7.64 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.21 (1H, d, J = 49Hz), 5.16-5.06(1H, m), 4.83-4.72(1H, m), 4.56-4.42(1H, m), 3.71-3.50(1H, m), 3.58(2H, s), 2.87-2.49( 4H, m), 2.43 (3H, s), 2.34-1.54 (16H, m), 1.14 (3H, s), 0.99 (3H, s), 0.68-0.57 (1H, m).

(Reference Example 1)

4,4-Difluorocyclohexanecarbaldehyde

At -55°C or lower temperature, 945ml (0.945mol) of 1.0M hydrogenated diisobutyl was added dropwise to a solution of 173g (0.900mol) of ethyl 4,4-difluorocyclohexanecarboxylate in 1.0L of toluene base aluminum-toluene solution, and then the reaction solution was stirred at -65°C for 30 minutes. After completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction solution at -40°C or lower, and then 1.0 L of 4N hydrochloric acid was added at 0°C or lower. The organic layer was separated, and the aqueous layer was extracted with toluene, and the combined organic layers were washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting oily residue (55-57°C/6mmHg) was distilled under reduced pressure to obtain 75.3 g of the title compound as a colorless oil (yield: 57%).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 9.68 (1H, d, J=1Hz), 2.42-2.28 (1H, m), 2.16-1.70 (8H, m).

(Reference Example 2)

tert-butyl 4-(1-amino-2-cyanovinyl)piperidine-1-carboxylate

Add 47.7ml (85.9mmol) of 1.8M lithium diisopropylamide-n-heptane/tetrahydrofuran/ethylbenzene solution to 50ml tetrahydrofuran and add 4.14ml (79.3mmol) of acetonitrile dropwise under cooling with a dry ice-acetone bath, And the reaction solution was stirred for 3.0 hours. Under the same conditions, a solution of 13.9g (66.1mmol) tert-butyl 4-cyanopiperidine-1-carboxylate in 30ml tetrahydrofuran was further added dropwise, and the reaction solution was stirred for 24 hours while slowly increasing the concentration of the reaction solution. temperature to room temperature. After the reaction was completed, ice water was added to the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=90/10-50/50 (V/V)], and concentrated under reduced pressure containing the desired As part of the compound, 10.7 g of the title compound was obtained as a yellow oil (yield: 64%).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 4.65 (2H, brs), 4.34-4.15 (2H, m), 3.87 (1H, s), 2.77-2.59 (2H, m), 2.16 (1H, tt , J=12, 4Hz), 1.84-1.73 (2H, m), 1.53-1.40 (2H, m), 1.46 (9H, s).

Mass Spectrum (EI, m/z): 251[M ⁺ ].

(Reference Example 3)

2-[(1-tert-butyloxycarbonyl)piperidin-4-yl]-3-cyano-4-(4,4-difluorocyclohexyl)-7,7-dimethyl-5-oxo Dai-1,4,5,6,7,8-hexahydroquinoline

To 14.6 g (57.9 mmol) of 4,4-difluorocyclohexane formaldehyde solution prepared by a method similar to the method of Reference Example 1 in 174 ml of toluene was added 12.8 g (69.7 mmol) tert-butyl 4-(1-amino-2-cyanoethenyl)-piperidine-1-carboxylate. After stirring under heating at 100° C. for 10 minutes, 9.74 g (69.5 mmol) of dimedone was added thereto and the reaction solution was stirred under reflux heating for 5 hours. Further, 2.43 g (17.3 mmol) of dimedone was added thereto and the reaction solution was stirred under reflux heating for 10 hours. After the reaction was completed, a precipitate was obtained by filtration to obtain 17.9 g of the title compound as a white solid (yield: 60%).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 6.27 (1H, s), 4.36-4.13 (2H, m), 3.70 (1H, d, J=2Hz), 3.03 (1H, tt, J=12, 3Hz), 2.91-2.73(2H, m), 2.40-2.19(5H, m), 2.17-1.98(2H, m), 1.84-1.40(9H, m), 1.48(9H, s), 1.35-1.20( 1H, m), 1.10(3H, s), 1.09(3H, s).

Mass Spectrum (CI, m/z): 504[(M+1) ⁺ ].

(Reference Example 4)

2-[(1-tert-butyloxycarbonyl)piperidin-4-yl]-3-cyano-4-(4,4-difluorocyclohexyl)-7,7-dimethyl-5-oxo Dai-5,6,7,8-tetrahydroquinoline

To 26.9 g (53.4 mmol) of 2-[(1-tert-butyloxycarbonyl)piperidin-4-yl]-3-cyano-4-(4 , 4-difluorocyclohexyl)-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline solution in 150ml dichloromethane added 18.2g ( 80.0 mmol) 2,3-dichloro-5,6-dicyano-p-benzoquinone, and the reaction solution was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was filtered through Celite (trade name), and the filtrate was washed with saturated aqueous sodium bicarbonate solution. The obtained organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Methanol was added to the obtained residue, and a precipitate was obtained by filtration to obtain 20.7 g of the title compound as a white solid (yield: 87%).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 4.38-4.15 (2H, m), 4.13-3.97 (1H, m), 3.38 (1H, tt, J=11, 4Hz), 3.06 (2H, s) , 2.97-2.80(2H, m), 2.69-2.52(2H, m), 2.61(2H, s), 2.33-2.17(2H, m), 2.01-1.72(8H, m), 1.48(9H, s) , 1.11(6H, s).

Mass Spectrum (EI, m/z): 501[M ⁺ ].

(Reference Example 5)

2-[(1-tert-butyloxycarbonyl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-formyl-7,7-dimethyl-5,6 , 7,8-tetrahydroquinolin-5-ol

At -50°C, to 20.1 g (40.0 mmol) of 2-[(1-tert-butyloxycarbonyl)piperidin-4-yl prepared by a method similar to that of Reference Example 4 in 300 ml of toluene A solution of ]-3-cyano-4-(4,4-difluorocyclohexyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline was added dropwise 100ml (100mmol) of 1.0M diisobutylaluminum hydride-toluene solution was stirred at the same temperature for 2 hours. Further, 100 ml (100 mmol) of a 1.0 M diisobutylaluminum hydride-toluene solution was added dropwise at the same temperature, and the temperature of the reaction solution was raised to -21° C. and the reaction solution was stirred for 2 hours. After completion of the reaction, the reaction solution was poured into a mixed solution of 6N hydrochloric acid, ice and ethyl acetate, and the mixture was vigorously stirred. After separation, the obtained organic layer was filtered to remove gel matter therein, washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Methanol was added to the obtained residue, and a precipitate was obtained by filtration to obtain 10.6 g of the title compound as a white solid (yield: 52%).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 10.81 (1H, s), 5.09 (1H, q, J=6Hz), 4.32-4.09 (2H, m), 3.53-3.37 (1H, m), 3.11 (1H, tt, J=11, 4Hz), 2.97-2.56(2H, m), 2.88(1H, d, J=17Hz), 2.65(1H, d, J=17Hz), 2.31-1.50(15H, m ), 1.47(9H, s), 1.15(3H, s), 1.00(3H, s).

Mass spectrum (CI, m/z): 507[(M+1) ⁺ ].

(Reference Example 6)

2-[(1-tert-butyloxycarbonyl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-formyl-5-[(4-methoxybenzyl )Oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline

Under ice cooling, to a solution of 0.846 g (19.4 mmol) of sodium hydride (55% dispersion in mineral oil) in 19 ml of N,N-dimethylformamide was added via a method similar to that of Reference Example 5. 9.63 g (19.0 mmol) of 2-[(1-tert-butyloxycarbonyl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-formyl-7,7 were prepared - a solution of dimethyl-5,6,7,8-tetrahydroquinolin-5-ol in 50 ml of N,N-dimethylformamide, and the reaction solution was stirred for 0.5 hour. Then, 2.7 ml (19 mmol) of p-methoxybenzyl bromide was added thereto, and the reaction solution was stirred under ice-cooling and then at room temperature for 1.5 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=90/10-70/30 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 6.97 g of The title compound as a white solid (Yield: 49%).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 10.76 (1H, s), 7.23 (2H, d, J = 9Hz), 6.86 (2H, d, J = 9Hz), 4.80 (1H, dd, J = 9, 5Hz), 4.77 (1H, d, J = 11Hz), 4.36 (1H, d, J = 11Hz), 4.29-4.08 (2H, m), 3.79 (3H, s), 3.14-2.67 (3H, m ), 3.08(1H, tt, J=11, 3Hz), 2.92(1H, d, J=17Hz), 2.67(1H, d, J=17Hz), 2.26-1.50(14H, m), 1.47(9H, s), 1.19(3H, s), 1.04(3H, s).

Mass Spectrum (CI, m/z): 627[(M+1) ⁺ ].

(Reference Example 7)

2-[(1-tert-butyloxycarbonyl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{hydroxyl[4-(trifluoromethyl)phenyl] Methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline

Under ice-cooling, to 7.52 g (12.0 mmol) in 60 ml of tetrahydrofuran, 2-[(1-tert-butyloxycarbonyl)piperidin-4-yl]- 4-(4,4-difluorocyclohexyl)-3-formyl-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8- A solution of tetrahydroquinoline was added dropwise to a solution of 4-trifluoromethylphenylmagnesium bromide prepared from 16.5 g (73.5 mmol) of 4-trifluoromethylphenyl bromide, 1.70 g (70.0 mmol) of magnesium and 140 ml of tetrahydrofuran. 48ml (equivalent to 24.0mmol) tetrahydrofuran solution. After completion of the above dropwise addition, the reaction solution was stirred at room temperature for 2.3 hours. After the reaction was completed, the reaction solution was added to a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=90/10-70/30 (V/V)] three times to obtain the initial eluate of diastereomer 1 as a foam and as the title 3.18 g (yield: 34%) of late eluate of diastereomer 2 of the compound as a foam. [Diastereomer 1]

Rf value: 0.29[n-hexane/ethyl acetate=7/3(V/V)].

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 7.57 (2H, d, J=8Hz), 7.37 (2H, d, J=8Hz), 7.25 (2H, d, J=9Hz), 6.87 (2H, d, J = 9Hz), 6.43 (1H, s), 4.83 (1H, d, J = 11Hz), 4.81 (1H, t, J = 5Hz), 4.38 (1H, d, J = 11Hz), 4.25-4.02 (1H, m), 3.83-3.75(1H, m), 3.80(3H, s), 3.24-2.42(3H, m), 2.86(1H, d, J=17Hz), 2.65(1H, d, J= 17Hz), 2.29-1.52(15H, m), 1.41(9H, s), 1.20(3H, s), 1.09(3H, s), 0.50-0.40(1H, m).

Mass Spectrum (CI, m/z): 773[(M+1) ⁺ ].

[Diastereomer 2]

Rf value: 0.21[n-hexane/ethyl acetate=7/3(V/V)].

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 7.56 (2H, d, J=8Hz), 7.39 (2H, d, J=8Hz), 7.26 (2H, d, J=9Hz), 6.88 (2H, d, J = 9Hz), 6.43 (1H, s), 4.83 (1H, t, J = 5Hz), 4.81 (1H, d, J = 11Hz), 4.39 (1H, d, J = 11Hz), 4.27-4.02 (1H, m), 3.84-3.70(1H, m), 3.80(3H, s), 3.23-2.47(3H, m), 2.86(1H, d, J=17Hz), 2.65(1H, d, J= 17Hz), 2.32-2.06(4H, m), 2.03-1.50(11H, m), 1.41(9H, s), 1.21(3H, s), 1.04(3H, s), 0.47-0.37(1H, m) .

Mass Spectrum (CI, m/z): 773[(M+1) ⁺ ].

(Reference Example 8)

2-[(1-tert-butyloxycarbonyl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl ]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline (diastereomer 2)

Under cooling with a dry ice-acetone bath, to 3.09 g (4.00 mmol) of 2-[(1-tert-butyloxycarbonyl)piperene prepared by a method similar to that of Reference Example 7 in 12 ml of dichloromethane Pyridin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{hydroxyl[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl Base)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline (diastereomer 2) solution was added to 1.47ml (8.00mmol) bis(methoxyethyl)amino sulfur trifluoride, and the reaction solution was stirred for 5.3 hours under the same conditions. Further, 0.15 ml (0.800 mmol) of bis(methoxyethyl)aminosulfur trifluoride was added thereto, and the reaction solution was stirred under the same conditions for 1 hour. After the reaction was completed, the reaction solution was added to a mixed solution of ice and saturated aqueous sodium bicarbonate solution and extracted with chloroform. The obtained organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Cyclohexane was added to the obtained residue, and a precipitate was obtained by filtration to obtain 2.55 g of the title compound as a white solid (yield: 82%).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 7.60 (2H, d, J=8Hz), 7.33 (2H, d, J=8Hz), 7.25 (2H, d, J=9Hz), 7.12 (1H, d, J = 49Hz), 6.87 (2H, d, J = 9Hz), 4.83 (1H, t, J = 5Hz), 4.81 (1H, d, J = 11Hz), 4.39 (1H, d, J = 11Hz) , 4.20-4.01(1H, m), 3.90-3.74(1H, m), 3.79(3H, s), 3.24-3.08(1H, m), 2.88(1H, d, J=17Hz), 2.68(1H, d, J=17Hz), 2.68-2.46 (2H, m), 2.32-2.08 (3H, m), 2.00-1.37 (11H, m), 1.41 (9H, s), 1.21 (3H, s), 1.05 ( 3H, s), 0.63-0.51 (1H, m).

Mass Spectrum (CI, m/z): 775[(M+1) ⁺ ].

(Reference Example 9)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]- 7,7-Dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline (diastereomer 2)

To 387 mg (0.500 mmol) of 2-[(1-tert-butyloxycarbonyl)piperidin-4-yl]-4- (4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7, 236 mg (1.05 mmol) of zinc bromide was added to the solution of 7-dimethyl-5,6,7,8-tetrahydroquinoline (diastereomer 2), and the reaction solution was stirred at 30°C for 68.5 hours. After the reaction was completed, the reaction solution was subjected to aminopropyl-modified silica gel column chromatography [n-hexane/ethyl acetate/methanol=50/50/0-0/100/0-0/90/10 (V/V/ V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 320 mg of the title compound as a foam (yield: 95%).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 7.60 (2H, d, J=8Hz), 7.33 (2H, d, J=8Hz), 7.25 (2H, d, J=9Hz), 7.11 (1H, d, J = 47Hz), 6.87 (2H, d, J = 9Hz), 4.83 (1H, t, J = 5Hz), 4.81 (1H, d, J = 11Hz), 4.39 (1H, d, J = 11Hz) , 3.79(3H, s), 3.23-2.98(2H, m), 2.95-2.55(4H, m), 2.48(1H, td, J=12, 2Hz), 2.33-2.08(3H, m), 2.01- 1.47(11H, m), 1.22(3H, s), 1.06(3H, s), 0.62-0.51(1H, m).

Mass Spectrum (CI, m/z): 675[(M+1) ⁺ ].

(Reference Example 10)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl) Oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline

With high performance liquid chromatography [CHIRALPAK (trade name) AD-H5cmID x25cmL (manufactured by Daicel Chemical Industry Co., Ltd.), eluent: n-hexane/2-propanol/isopropylamine=80/20/0.1 (V/V/V )] optical resolution of 10g4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl prepared by a method similar to the method of Reference Example 9 }-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline ( Diastereomer 2) afforded 4.2 g of the late eluate of the title compound as a white solid and 4.4 g of the early eluate of the enantiomer as a white solid, respectively.

[title compound]

Specific rotation: [α] _D ²⁴ = -101° (C = 0.25, methanol).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δppm: 7.61 (2H, d, J = 8Hz), 7.35 (2H, d, J = 8Hz), 7.26 (2H, d, J = 9Hz), 7.14 ( 1H, d, J = 47Hz), 6.86 (2H, d, J = 9Hz), 4.85 (1H, t, J = 5Hz), 4.80 (1H, d, J = 11Hz), 4.39 (1H, d, J = 11Hz), 3.77(3H, s), 3.25-3.09(1H, m), 3.03-2.93(1H, m), 2.92-2.80(1H, m), 2.75-2.53(3H, m), 2.45(1H, td, J=12, 3Hz), 2.30-2.11(3H, m), 2.00-1.39(11H, m), 1.20(3H, s), 1.07(3H, s), 0.61-0.51(1H, m).

Mass Spectrum (CI, m/z): 675[(M+1) ⁺ ].

Analytical conditions of high performance liquid chromatography:

Column: CHIRALPAK (trade name) AD-H (0.46cm ID×25cm, manufactured by Daicel Chemical Co., Ltd.)

Eluent: n-hexane/2-propanol/isopropylamine=80/20/0.1(V/V/V)

Flow rate: 1.0ml/min

Column temperature: 40°C

Detection wavelength: 271nm

Hold time: 5.5 minutes

[enantiomer of title compound]

Specific rotation: [α] _D ²⁴ =100° (C=0.25, methanol).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δppm: 7.61 (2H, d, J = 8Hz), 7.35 (2H, d, J = 8Hz), 7.26 (2H, d, J = 9Hz), 7.14 ( 1H, d, J = 47Hz), 6.86 (2H, d, J = 9Hz), 4.85 (1H, t, J = 5Hz), 4.80 (1H, d, J = 11Hz), 4.39 (1H, d, J = 11Hz), 3.77(3H, s), 3.25-3.08(1H, m), 3.04-2.92(1H, m), 2.91-2.80(1H, m), 2.76-2.53(3H, m), 2.45(1H, td, J=12, 3Hz), 2.28-2.10(3H, m), 2.00-1.39(11H, m), 1.20(3H, s), 1.07(3H, s), 0.61-0.50(1H, m).

Mass Spectrum (CI, m/z): 675[(M+1) ⁺ ].

Analytical conditions of high performance liquid chromatography:

Column: CHIRALPAK (trade name) AD-H (0.46cm ID×25cm, manufactured by Daicel Chemical Co., Ltd.)

Eluent: n-hexane/2-propanol/isopropylamine=80/20/0.1(V/V/V)

Flow rate: 1.0ml/min

Column temperature: 40°C

Detection wavelength: 271nm

Retention time: 4.0 minutes

(Reference Example 11)

(-)-2-[1-(5-bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(tri Fluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline

4.80 g (7.11 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3 prepared by a method similar to that of Reference Example 10 in 16 ml of 1,4-dioxane -{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidine- 4-yl)-5,6,7,8-tetrahydroquinoline solution was added with 1.40g (7.24mmol) 5-bromo-2-chloropyrimidine and 1.6ml (9.4mmol) diisopropylethylamine, at 80°C The reaction solution was stirred for 3 hours. After the reaction was completed, the reaction solution was poured into 40 ml of 0.5N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium chloride solution, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. To the obtained residue was added n-heptane, and a precipitate was obtained by filtration to obtain 5.09 g of the title compound as a white solid (yield: 86%).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δppm: δ: 8.22 (2H, s), 7.64 (2H, d, J = 8Hz), 7.38 (2H, d, J = 8Hz), 7.26 (2H, d, J = 9Hz), 7.17 (1H, d, J = 46Hz), 6.86 (2H, d, J = 9Hz), 4.85 (1H, t, J = 5Hz), 4.80 (1H, d, J = 11Hz) , 4.75-4.63(1H, m), 4.48-4.38(1H, m), 4.39(1H, d, J=11Hz), 3.77(3H, s), 3.26-3.07(1H, m), 2.90-2.55( 4H, m), 2.32-1.35 (14H, m), 1.17 (3H, s), 1.04 (3H, s), 0.74-0.61 (1H, m).

(Reference Example 12)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl) Oxygen]-7,7-dimethyl-2-{1-[5-(morpholin-4-yl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8- Tetrahydroquinoline

Under an argon atmosphere, to 5.09 g (6.12 mmol) of (-)-2-[1-(5-bromopyrimidin-2-yl)piper in 50 ml of toluene prepared by a method similar to that of Reference Example 11 Pyridin-4-yl]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxy Benzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline solution was added with 10ml tert-butanol, 1.6ml (18mmol) morpholine, 1.73g (18.0mmol) tert-butyl Sodium oxide, 437 mg (0.917 mmol) of 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl and 107 mg (0.477 mmol) of palladium acetate were stirred at 110°C for 2.8 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=8/2-7/3-6/4 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure, 4.30 g of the title compound were obtained as a white solid (yield: 84%).

Specific rotation: [α] _D ²⁸ = -119° (C = 0.645, chloroform).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δppm: 8.03 (2H, s), 7.63 (2H, d, J = 8Hz), 7.38 (2H, d, J = 8Hz), 7.26 (2H, d, J = 9Hz), 7.17 (1H, d, J = 46Hz), 6.86 (2H, d, J = 9Hz), 4.85 (1H, t, J = 5Hz), 4.80 (1H, d, J = 11Hz), 4.70 -4.60(1H, m), 4.43-4.32(1H, m), 4.39(1H, d, J=11Hz), 3.86-3.71(4H, m), 3.77(3H, s), 3.26-3.09(1H, m), 3.02-2.89 (4H, m), 2.87-2.57 (4H, m), 2.33-1.45 (14H, m), 1.18 (3H, s), 1.04 (3H, s), 0.72-0.59 (1H, m).

(Reference Example 13)

4-(4,4-difluorocyclohexyl)-2-(1-{5-[4-(ethoxycarbonyl)piperidin-1-yl]pyrimidin-2-yl}piperidin-4-yl- 3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7 , 8-Tetrahydroquinoline

To 250 mg (0.301 mmol) of (-)-2-[1-(5-bromopyrimidin-2-yl)piperidin-4-yl prepared by a method similar to that of Reference Example 11 in 1.5 ml of toluene ]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy ]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline solution was added 61mg (0.39mmol) ethyl isopiperidine, 38mg (0.075mmol) 5-(di-tert-butylphosphine base)-1',3',5'-triphenyl-1'H-[1,4']bipyrazole, 38mg (0.39mmol) sodium tert-butoxide and 28mg (0.030mmol) tris(dibenzylidene Dipalladium (0), stirring the reaction solution at 100° C. for 40 minutes while irradiating with microwaves using a microwave reactor (product name: Initiator, manufactured by Biotage). After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=85/15-65/35 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 98 mg as shallow The title compound as a brown solid (Yield: 36%).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.05 (2H, s), 7.61 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.26 (2H, d, J = 9Hz), 7.15(1H, d, J=47Hz), 6.87(2H, d, J=9Hz), 4.86-4.76(2H, m), 4.71-4.62(1H, m), 4.43-4.34(2H, m ), 4.16(2H, q, J=7Hz), 3.79(3H, s), 3.34-3.08(3H, m), 2.88-2.58(6H, m), 2.42-1.49(19H, m), 1.27(3H , t, J=7Hz), 1.19(3H, s), 1.04(3H, s), 0.70-0.60(1H, m).

Mass spectrum (FAB, m/z): 907[M ⁺ ].

(Reference Example 14)

2-Chloro-5-(methylsulfonyl)pyrimidine

To a solution of 80 mg (0.50 mmol) of 2-chloro-5-methylthiopyrimidine prepared in a manner similar to that of Reference Example 36 in 2.5 ml of dichloromethane was added 264 mg (1.0 mmol) of 3-chloro-perphenyl Formic acid (purity: 65%), the reaction solution was stirred at room temperature for 90 minutes. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the reaction solution was extracted with dichloromethane. The organic layer was washed with a 1.5 mol/L sodium sulfite aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=70/30-40/60 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 80 mg as white The title compound as a solid (yield: 82%).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 9.11 (2H, s), 3.19 (3H, s).

(Reference Example 15)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]- 7,7-Dimethyl-2-[1-(pyrimidin-2-yl)piperidin-4-yl]-5,6,7,8-tetrahydroquinoline

To 1.21 g (1.79 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl) prepared by a method similar to that of Reference Example 10 Phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8- Add 0.90 g (5.7 mmol) of 2-bromopyrimidine, 1.0 ml (5.9 mmol) of diisopropylethylamine and 20 ml of tert-butanol to tetrahydroquinoline, and stir the reaction solution at 65° C. for 2.5 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. n-Hexane was added to the resulting residue, and a precipitate was obtained by filtration to obtain 1.17 g of the title compound as a white solid (yield: 87%).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δppm: 8.22 (2H, d, J = 5Hz), 7.64 (2H, d, J = 8Hz), 7.38 (2H, d, J = 8Hz), 7.26 ( 2H, d, J = 9Hz), 7.18 (1H, d, J = 46Hz), 6.86 (2H, d, J = 9Hz), 6.39 (1H, t, J = 5Hz), 4.85 (1H, t, J = 5Hz), 4.81-4.72(1H, m), 4.80(1H, d, J=11Hz), 4.56-4.44(1H, m), 4.39(1H, d, J=11Hz), 3.77(3H, s), 3.26-3.10(1H, m), 2.90-2.56(4H, m), 2.32-2.02(4H, m), 2.00-1.31(10H, m), 1.17(3H, s), 1.04(3H, s), 0.74-0.62(1H, m).

Mass Spectrum (CI, m/z): 753[(M+1) ⁺ ].

(Reference Example 16)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-formylpyrimidin-2-yl) Piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline

To 1.00 g (1.48 mmol) (-)-4-(4,4-difluorocyclohexyl)-3-{ Fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidine-4- Base)-5,6,7,8-tetrahydroquinoline solution was added with 0.23g (1.6mmol) 2-chloro-5-formylpyrimidine and 265μl (1.78mmol) diazabicycloundecene, stirred at room temperature The reaction solution was reacted for 1 hour. Then, 0.023 g (0.16 mmol) of 2-chloro-5-formylpyrimidine was added thereto, and the reaction solution was further stirred at room temperature for 0.58 hours. Furthermore, 0.023 g (0.16 mmol) of 2-chloro-5-formylpyrimidine was added thereto, and the reaction solution was stirred at room temperature for 1.5 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=40/10 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 1.00 g of The title compound (yield: 87%).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 9.71 (1H, s), 8.65 (2H, s), 7.63 (2H, d, J=8Hz), 7.37 (2H, d, J=8Hz), 7.25 (2H, d, J = 9Hz), 7.16 (1H, d, J = 48Hz), 6.87 (2H, d, J = 9Hz), 5.03-4.91 (1H, m), 4.83 (1H, t, J = 5Hz ), 4.81(1H, d, J=11Hz), 4.77-4.67(1H, m), 4.39(1H, d, J=11Hz), 3.79(3H, s), 3.25-3.09(1H, m), 2.92 -2.74(2H, m), 2.84(1H, d, J=17Hz), 2.65(1H, d, J=17Hz), 2.34-1.46(14H, m), 1.19(3H, s), 1.03(3H, s), 0.79-0.68(1H, m).

Mass Spectrum (EI, m/z): 780[M ⁺ ].

(Reference Example 17)

(-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-[5-(hydroxymethyl )pyrimidin-2-yl]piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinone phylloline

Under ice-cooling, in a mixture of 5 ml of ethanol and 5 ml of tetrahydrofuran, 500 mg (0.64 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro Substitute [4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-formylpyrimidin-2-yl)piperidin-4-yl]-5-[(4-methoxy Benzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline solution was added with 12 mg (0.32 mmol) of sodium borohydride, and the reaction solution was stirred for 0.83 hours under ice cooling. After the reaction was completed, the solvent was distilled off under reduced pressure, 1N hydrochloric acid and 1N aqueous sodium hydroxide solution were added successively, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.52 g of the title compound as a white foam (yield: quantitative).

Specific rotation: [α] _D ²⁸ = -125° (C = 0.600, chloroform).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 8.25 (2H, s), 7.62 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.25 (2H, d, J = 9Hz), 7.15(1H, d, J=47Hz), 6.87(2H, d, J=9Hz), 4.85-4.74(1H, m), 4.83(1H, t, J=5Hz), 4.81(1H, d , J=11Hz), 4.57-4.44(3H, m), 4.39(1H, d, J=11Hz), 3.79(3H, s), 3.25-3.08(1H, m), 2.90-2.59(4H, m) , 2.33-2.06(4H, m), 2.01-1.42(11H, m), 1.19(3H, s), 1.03(3H, s), 0.72-0.62(1H, m).

Mass Spectrum (EI, m/z): 782[M ⁺ ].

(Reference Example 18)

2-{1-[5-(cyclohex-1-en-1-yl)pyrimidin-2-yl]piperidin-4-yl}-4-(4,4-difluorocyclohexyl)-3-{ Fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8- Tetrahydroquinoline

Under an argon atmosphere, to 97 mg (0.12 mmol) of (-)-2-[1-(5-bromopyrimidin-2-yl)piperidin-4-yl] prepared by a method similar to that of Reference Example 11 -4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy] -7,7-dimethyl-5,6,7,8-tetrahydroquinoline was added with 114mg (1.19mmol) sodium tert-butoxide, 26mg (0.055mmol) 2-dicyclohexylphosphino-2', 4',6'-triisopropylbiphenyl, 3.4mg (0.0l5mmol) palladium acetate, 3ml toluene, 1.5ml tert-butanol and 100μl (0.471mmol) cyclohexenylboronic acid pinacol ester, stirred at 120°C The reaction solution was left for 5 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was mixed with 99 mg (0.12 mmol) of (-)-2-[1-(5-bromopyrimidin-2-yl)piperidin-4-yl]-4-(4,4-difluorocyclohexyl )-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6 , 7,8-tetrahydroquinoline carry out the residue that similar reaction obtains to combine, make them through silica gel column chromatography [n-hexane/ethyl acetate=100/0-95/5-92/8-88/12 ( V/V)], and the fraction containing the desired compound was concentrated under reduced pressure to obtain 80 mg of the title compound as a white solid (yield: 41%).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δppm: 8.27 (2H, s), 7.64 (2H, d, J = 8Hz), 7.38 (2H, d, J = 8Hz), 7.26 (2H, d, J=9Hz), 7.17(1H, d, J=45Hz), 6.86(2H, d, J=9Hz), 6.02-5.91(1H, m), 4.85(1H, t, J=5Hz), 4.81-4.70 (1H, m), 4.80(1H, d, J=11Hz), 4.54-4.44(1H, m), 4.39(1H, d, J=11Hz), 3.77(3H, s), 3.26-3.10(1H, m), 2.91-2.54(4H, m), 2.39-1.46(22H, m), 1.17(3H, s), 1.04(3H, s), 0.74-0.61(1H, m).

(Reference Example 19)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(1-hydroxy-2-methyl Propyl)pyrimidin-2-yl]piperidin-4-yl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8- Tetrahydroquinoline

Under an argon atmosphere, 213 mg (0.273 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4- (Trifluoromethyl)phenyl]methyl}-2-[1-(5-formylpyrimidin-2-yl)piperidin-4-yl]-5-[(4-methoxybenzyl)oxy Base]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline solution was added to 0.5ml (0.5mmol) 1.0mol/L isopropylmagnesium bromide-tetrahydrofuran solution, and the reaction was stirred at room temperature solution for 0.5 hours. Then, 0.5 ml (0.5 mmol) of a 1.0 mol/L isopropylmagnesium bromide-tetrahydrofuran solution was further added, and the reaction solution was stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=85/15-80/20 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 174 mg as white The title compound as a solid (Yield: 77%).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δppm: 8.18 (2H, s), 7.64 (2H, d, J = 8Hz), 7.38 (2H, d, J = 8Hz), 7.26 (2H, d, J=9Hz), 7.18(1H, d, J=45Hz), 6.86(2H, d, J=9Hz), 4.85(1H, t, J=5Hz), 4.81-4.71(1H, m), 4.80(1H , d, J=11Hz), 4.54-4.45(1H, m), 4.39(1H, d, J=11Hz), 4.19(1H, d, J=7Hz), 3.77(3H, s), 3.26-3.10( 1H, m), 2.89-2.57 (4H, m), 2.29-1.44 (16H, m), 1.17 (3H, s), 1.04 (3H, s), 0.97 (3H, d, J=7Hz), 0.79 ( 3H, d, J=7Hz), 0.72-0.63 (1H, m).

(Reference Example 20)

Methyl 5-(2-chloropyrimidin-5-yl)pentanoate

To a solution of 500 mg (2.58 mmol) 5-bromo-2-chloropyrimidine in 10 ml of N, N-dimethylformamide, add a solution of 397 mg (3.54 mmol) of methyl4-pentenoate (methyl4-pentinoate), 49 mg (0.26 mmol) of copper iodide, 149 mg (0.129 mmol) of tetrakis (triphenylphosphine) palladium (0) and 5.0 ml of triethylamine was added, and the reaction solution was stirred at 80°C for 4 hours. After the reaction was completed, saturated aqueous ammonium chloride solution was added to the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=93/7-75/25 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 347 mg ( Yield: 60%) methyl 5-(2-chloropyrimidin-5-yl)-4-pentenoate.

To a solution of 337 mg (1.50 mmol) of methyl 5-(2-chloropyrimidin-5-yl)-4-pentenoate obtained above in 7 ml of ethyl acetate was added 70 mg of 10% palladium on carbon, at room temperature under a hydrogen atmosphere The reaction solution was stirred for 20 hours. The catalyst was removed by filtration, and then the solvent was distilled off under reduced pressure to obtain 177 mg of the title compound as a colorless oil (yield: 52%).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.46 (2H, s), 3.68 (3H, s), 2.63 (2H, t, J=7Hz), 2.36 (2H, t, J=7Hz), 1.74 -1.63(4H, m).

Mass Spectrum (EI, m/z): 228[M ⁺ ].

(Reference Example 21)

4-(4,4-difluorocyclohexyl)-2-{1-[5-(ethoxymethyl)pyrimidin-2-yl]piperidin-4-yl}-3-{fluoro[4- (Trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline

To 78 mg (0.10 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4 -(trifluoromethyl)phenyl]methyl}-2-[1-[5-(hydroxymethyl)pyrimidin-2-yl]piperidin-4-yl]-5-[(4-methoxy Benzyl)oxyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline solution was added with 340 μl (2.0 mmol) diisopropylethylamine and 77 μl (1.0 mmol) methanesulfonyl chloride, Immediately after stirring was started at room temperature, 2 ml of ethanol was added thereto, and the reaction solution was further stirred at room temperature for 0.25 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=98/2-70/30 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 68 mg as a foam The title compound (yield: 85%).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 8.22 (2H, s), 7.62 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.25 (2H, d, J = 9Hz), 7.15(1H, d, J=48Hz), 6.87(2H, d, J=9Hz), 4.87-4.73(2H, m), 4.81(1H, d, J=11Hz), 4.56-4.46(1H , m), 4.38(1H, d, J=11Hz), 4.28(2H, s), 3.79(3H, s), 3.48(2H, q, J=7Hz), 3.24-3.08(1H, m), 2.91 -2.59(4H, m), 2.31-2.05(4H, m), 2.02-1.47(10H, m), 1.21(3H, t, J=7Hz), 1.19(3H, s), 1.03(3H, s) , 0.70-0.60 (1H, m).

Mass Spectrum (EI, m/z): 810[M ⁺ ].

(Reference Example 22)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]- 2-{1-[5-(Methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinoline

Except using methanol instead of ethanol and from 72 mg (0.092 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl) prepared by a method similar to that of Reference Example 17 Base) phenyl] methyl}-2-[1-[5-(hydroxymethyl)pyrimidin-2-yl]piperidin-4-yl]-5-[(4-methoxybenzyl)oxy ]-7,7-Dimethyl-5,6,7,8-Tetrahydroquinoline, except starting, carried out reactions similar to those of Reference Example 21 to obtain 48 mg of the title compound as a foam (yield: 66% ).

¹ H-NMR spectrum 300MHz, CD ₂ Cl ₂ ) δppm: 8.19 (2H, s), 7.64 (2H, d, J = 8Hz), 7.38 (2H, d, J = 8Hz), 7.26 (2H, d, J =9Hz), 7.18(1H, d, J=48Hz), 6.86(2H, d, J=9Hz), 4.89-4.72(1H, m), 4.85(1H, t, J=5Hz), 4.80(1H, d,J=11Hz), 4.56-4.46(1H,m), 4.39(1H,d,J=11Hz), 4.20(2H,s), 3.77(3H,s), 3.29(3H,s), 3.24- 3.09(1H,m), 2.89-2.58(4H,m), 2.29-2.03(4H,m), 2.00-1.46(10H,m), 1.17(3H,s), 1.04(3H,s), 0.72- 0.63(1H, m).

Mass Spectrum (EI, m/z): 796[M ⁺ ].

(Reference Example 23)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]- 7,7-Dimethyl-2-(1-{5-[(prop-2-yloxy)methyl]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8 -Tetrahydroquinoline

Except that isopropanol was used instead of ethanol and 78 mg (0.10 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(tri Fluoromethyl)phenyl]methyl}-2-[1-[5-(hydroxymethyl)pyrimidin-2-yl]piperidin-4-yl]-5-[(4-methoxybenzyl) Oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, except starting from the reaction analogous to those of Reference Example 21, afforded 54 mg of the title compound as a foam (yield: 65%).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 8.22 (2H, s), 7.62 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.25 (2H, d, J = 9Hz), 7.15(1H, d, J=48Hz), 6.87(2H, d, J=9Hz), 4.86-4.72(1H, m), 4.82(1H, t, J=5Hz), 4.81(1H, d , J=11Hz), 4.55-4.46(1H, m), 4.38(1H, d, J=11Hz), 4.28(2H, s), 3.79(3H, s), 3.64(1H, dq, J=6, 6Hz), 3.22-3.08(1H, m), 2.91-2.60(4H, m), 2.31-2.05(4H, m), 2.01-1.46(10H, m), 1.19(3H, s), 1.18(6H, d, J=6Hz), 1.03(3H, s), 0.70-0.59(1H, m)

Mass Spectrum (EI, m/z): 824[M ⁺ ].

(Reference Example 24)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]- 7,7-Dimethyl-2-(1-{5-[(2-methylpropoxy)methyl]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8 -Tetrahydroquinoline

Except that isobutanol was used instead of ethanol and 78 mg (0.10 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(tri Fluoromethyl)phenyl]methyl}-2-[1-[5-(hydroxymethyl)pyrimidin-2-yl]piperidin-4-yl]-5-[(4-methoxybenzyl) Oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, except starting from the reaction analogous to those of Reference Example 21, afforded 59 mg of the title compound as a foam (yield: 70%).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 8.22 (2H, s), 7.62 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.25 (2H, d, J = 9Hz), 7.15(1H, d, J=47Hz), 6.87(2H, d, J=9Hz), 4.86-4.73(2H, m), 4.81(1H, d, J=11Hz), 4.57-4.47(1H , m), 4.39(1H, d, J=11Hz), 4.27(2H, s), 3.79(3H, s), 3.23-3.08(1H, m), 3.17(2H, d, J=7Hz), 2.91 -2.59(4H, m), 2.32-2.06(4H, m), 1.99-1.49(11H, m), 1.19(3H, s), 1.03(3H, s), 0.89(6H, d, J=7Hz) , 0.71-0.61 (1H, m).

Mass Spectrum (EI, m/z): 838[M ⁺ ].

(Reference Example 25)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]- 7,7-Dimethyl-2-{1-[5-(methylcarbamoyl)pyrimidin-2-yl]piperidin-4-yl}-5,6,7,8-tetrahydroquinoline

To 391 mg (0.501 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methanol prepared by a method similar to that of Reference Example 16 Base}-2-[1-(5-formylpyrimidin-2-yl)piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl -5,6,7,8-tetrahydroquinoline was added with 3.0ml tetrahydrofuran, 1.5ml tert-butanol, 0.6ml water, 1.2ml 2-methyl-2-butene, 391mg (2.50mmol) sodium dihydrogen phosphate and 226mg (2.50 mmol) sodium chlorite, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution was added to the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 465 mg of crude product 2-[1-(5-carboxypyrimidin-2-yl)piperidin-4-yl ]-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy ]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline.

To a solution of 70 mg of the obtained crude product in 0.5 ml of tetrahydrofuran was added 21 mg (0.13 mmol) of 1,1'-carbonyldiimidazole, and the reaction solution was stirred at room temperature for 30 minutes. 0.5 ml of about 40% aqueous methylamine solution was added to the reaction solution, and the reaction solution was further stirred at room temperature for 30 minutes. After the reaction was completed, water was added to the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product of the title compound.

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.61 (2H, s), 7.63 (2H, d, J = 8Hz), 7.36 (2H, d, J = 8Hz), 7.25 (2H, d, J = 9Hz), 7.16(1H, d, J=47Hz), 6.87(2H, d, J=9Hz), 5.88-5.79(1H, m), 4.91-4.76(2H, m), 4.81(1H, d, J =11Hz), 4.64-4.57(1H, m), 4.39(1H, d, J=11Hz), 3.79(3H, s), 3.22-3.10(1H, m), 2.97(3H, d, J=5Hz) , 2.89-2.59(4H, m), 2.32-1.49(14H, m), 1.19(3H, s), 1.03(3H, s), 0.73-0.64(1H, m).

(Reference Example 26)

2-Chloro-5-(4,4,4-trifluorobutyl)pyrimidine

By M. Zhang et al., Bioorganic and Medicinal Chemistry Letters, 2007, 17 volumes, 1.2g (2.4mmol) iodide (3,3,3-trifluoropropyl) triphenyl iodide synthesized by the method described in pages 2401-2403 A solution of phosphonium in 16 ml of tetrahydrofuran was cooled to 0°C and 1.6 ml (2.6 mmol) of a 1.7N n-butyllithium/n-hexane solution was added thereto, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0°C again, and then a solution of 0.31 g (2.2 mmol) of 2-chloropyrimidine-5-carbaldehyde in 4 ml of tetrahydrofuran was added to the reaction solution, and the reaction solution was stirred at room temperature for 30 minutes. After the reaction was completed, saturated aqueous ammonium chloride solution was added to the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=100/0-80/20 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 0.17 g of 2- Chloro-5-(4,4,4-trifluoro-1-buten-1-yl)pyrimidine.

To a solution of 0.17 g (0.78 mmol) of 2-chloro-5-(4,4,4-trifluoro-1-buten-1-yl)pyrimidine obtained above in 7 ml of ethanol was added 35 mg of 10% palladium on carbon at The reaction solution was stirred at room temperature under a hydrogen atmosphere for 45 minutes. The catalyst was removed by filtration, and then the solvent was distilled off under reduced pressure to obtain 0.14 g of the title compound as a colorless oil (yield: 30%).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.49 (2H, s), 2.72 (2H, t, J=8Hz), 2.23-2.09 (2H, m), 1.99-1.87 (2H, m).

(Reference Example 27)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(1-hydroxyl-3-methyl butyl)pyrimidin-2-yl]piperidin-4-yl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8- Tetrahydroquinoline

Under an argon atmosphere, 294 mg (0.377 mmol) of 4-(4,4-difluorocyclohexyl)-3-{fluoro[4- (Trifluoromethyl)phenyl]methyl}-2-[1-(5-formylpyrimidin-2-yl)piperidin-4-yl]-5-[(4-methoxybenzyl)oxy Add 0.5ml (0.5mmol) 1.0mol/L isobutylmagnesium bromide-tetrahydrofuran solution to the -7,7-dimethyl-5,6,7,8-tetrahydroquinoline solution, and stir the reaction at room temperature Solution for 0.17 hours. Then, 1.0 ml (1.0 mmol) of a 1.0 mol/L isobutylmagnesium bromide-tetrahydrofuran solution was further added thereto, and the reaction solution was stirred at room temperature for 0.33 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and then the solvent was distilled off under reduced pressure to obtain 328 mg of the title compound as a foam (yield: quantitative).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δppm: 8.22 (2H, s), 7.64 (2H, d, J = 8Hz), 7.38 (2H, d, J = 8Hz), 7.26 (2H, d, J=9Hz), 7.18(1H, d, J=47Hz), 6.86(2H, d, J=9Hz), 4.91-4.72(1H, m), 4.85(1H, t, J=5Hz), 4.80(1H , d, J=11Hz), 4.61-4.43 (2H, m), 4.39 (1H, d, J=11Hz), 3.77 (3H, s), 3.25-3.11 (1H, m), 2.89-2.57 (4H, m), 2.31-2.02 (4H, m), 1.99-1.42 (14H, m), 1.17 (3H, s), 1.04 (3H, s), 0.93 (6H, d, J=6Hz), 0.73-0.63 ( 1H, m).

Mass Spectrum (CI, m/z): 839[(M+1) ⁺ ].

(Reference Example 28)

2-Chloro-5-[(1-methylpiperidin-4-yl)oxy]pyrimidine

To a solution of 100 mg (0.766 mmol) 4-hydroxy-1-methylpiperidine in 1.5 ml tetrahydrofuran was added 155 mg (1.53 mmol) di-tert-butylazocarboxylic acid, 402 mg (1.53 mmol) triphenylphosphine and 0.170 ml ( 1.53 mmol) of 2-chloro-5-hydroxypyrimidine, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, ethyl acetate was added to the reaction solution, and the reaction solution was extracted with 1N hydrochloric acid. 1N Aqueous sodium hydroxide solution was added to the aqueous layer to bring the pH to 10, and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 152 mg of the title compound as a white solid (yield: 87%).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.22 (2H, s), 4.33 (1H, tt, J=7.5, 3.8Hz), 2.65-2.57 (2H, m), 2.30-2.22 (5H, m ), 2.01-1.93(2H, m), 1.85-1.75(2H, m).

(Reference Example 29)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]- 7,7-Dimethyl-2-(1-{5-[(1-methylpiperidin-4-yl)oxy]pyrimidin-2-yl}piperidin-4-yl)-5,6, 7,8-Tetrahydroquinoline

To 100 mg (0.155 mmol) (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[ 4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)- 5,6,7,8-Tetrahydroquinoline solution was added 71 mg (0.31 mmol) of 2-chloro-5-[(1-methylpiperidin-4-yl) prepared by a method similar to that of Reference Example 28 ) oxygen group] pyrimidine and 0.60ml (0.33mmol) N, N-diisopropylethylamine, stirred reaction solution 30 minutes at 160 ℃, simultaneously with microwave reactor (product name: initiator (Initiator), by Biotage Preparation) microwave irradiation. After the reaction was completed, the solvent of the reaction solution was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=100/0-20/80 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 102 mg of the title compound as a colorless oil from 16 mg of 2-chloro-5-[(1-methylpiperidin-4-yl)oxy]pyrimidine (yield: 64%).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.03 (2H, s), 7.62 (2H, d, J = 8Hz), 7.37 (2H, d, J = 8Hz), 7.26 (2H, d, J = 9Hz), 7.16(1H, d, J=47Hz), 6.88(2H, d, J=9Hz), 4.88-4.77(2H, m), 4.73-4.62(1H, m), 4.45-4.32(2H, m ), 4.05-3.95(1H, m), 3.79(3H, s), 3.22-3.10(1H, m), 2.93-2.57(6H, m), 2.37-1.52(23H, m), 1.20(3H, s ), 1.04(3H, s), 0.73-0.60(1H, m).

(Reference Example 30)

2-Chloro-5-{[(3R)-1-methylpyrrolidin-3-yl]oxy}pyrimidine

Similar to the reference example, except that (3S)-1-methyl-3-pyrrolidinol was used instead of 1-methyl-4-piperidinol and starting from 100 mg (0.766 mmol) 2-chloro-5-hydroxypyrimidine Reaction of those of 28 afforded 164 mg of the title compound as a white solid (yield: quantitative).

¹ H-NMR spectrum (400MHz, CDCl ₃ ) δppm: 8.25 (2H, s), 4.89-4.84 (1H, m), 2.93-2.86 (2H, m), 2.78 (1H, dd, J=11.0, 5.9Hz ), 2.45-2.34(5H, m), 2.05-1.97(1H, m).

(Reference Example 31)

2-Chloro-5-(3,3,3-trifluoropropoxy)pyrimidine

Similar to Reference Example 28, except that 3,3,3-trifluoro-1-propanol was used instead of 1-methyl-4-piperidinol and starting from 100 mg (0.693 mmol) 2-chloro-5-hydroxypyrimidine The reaction of those gave 144 mg of the title compound as a colorless oil (yield: 92%).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.33 (2H, s), 4.30 (2H, t, J=6.5Hz), 2.74-2.64 (2H, m).

(Reference Example 32)

2-Chloro-5-(difluoromethoxy)pyrimidine

To a solution of 93 mg (0.71 mmol) 4-hydroxyl-1-methylpiperidine in 1.0 ml N, N-dimethylformamide was added 0.28 g (0.86 mmol) cesium carbonate and 0.32 mg (2.2 mmol) monochlorodi Methyl fluoroacetate, and the reaction solution was stirred at 100°C for 1 hour. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer chromatography [n-hexane/ethyl acetate=75/25 (V/V)] to obtain 55 mg of the title compound as a colorless oil (yield: 43%).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.53 (2H, s), 6.62 (1H, t, J=71Hz). (Reference Example 33)

2-Chloro-5-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methoxy]pyrimidine

To the solution of 9.50g (72.8mmol) 2-chloro-5-hydroxypyrimidine in 100ml N,N-dimethylformamide, add 26.1g (80.1mmol) cesium carbonate and through V.W.Gash, Journal ofOrganic Chemistry, 1972,37 Volume, 24.3 g (102 mmol) of 5-(methylsulfonyloxymethyl)-2,2,5-trimethyl-1,3-dioxane synthesized by the method described in pages 2197-2201, The reaction solution was stirred at 90°C for 24 hours. After the reaction was completed, insoluble raw materials were filtered off, washed with ethyl acetate, and then 0.5N aqueous sodium hydroxide solution was added to the filtrate for separation. The resulting aqueous layer was further extracted with ethyl acetate. The obtained organic layers were combined, washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Toluene was added to the obtained residue, and the precipitate was filtered and washed with toluene and n-heptane to obtain 6.00 g of the title compound as a white solid (yield: 30%).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 8.34 (2H, s), 4.16 (2H, s), 3.73 (4H, s), 1.47 (3H, s), 1.41 (3H, s), 0.94 ( 3H, s).

(Reference Example 34)

4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]- 7,7-Dimethyl-2-(1-{5-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methoxy]pyrimidine-2- Base}piperidin-4-yl)-5,6,7,8-tetrahydroquinoline

To 599 mg (0.887 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(tri Fluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6, 7,8-Tetrahydroquinoline solution was added 242 mg (0.887 mmol) of 2-chloro-5-[(2,2,5-trimethyl-1,3- Dioxan-5-yl)methoxy]pyrimidine, 128mg (1.33mmol) sodium tert-butoxide, 26mg (0.044mmol) bis(dibenzylideneacetone) palladium (0) and 63mg (0.089mmol ) 1,2,3,4,5-pentylphenyl-1'-(di-tert-butylphosphino)ferrocene, and the reaction solution was stirred at 90° C. for 21 hours in an argon atmosphere. After the reaction was completed, water and a saturated aqueous sodium chloride solution were poured into the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=4/1 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 120 mg of the title compound as a brown oil (Yield: 15%).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 8.04 (2H, s), 7.61 (2H, d, J = 8Hz), 7.35 (2H, d, J = 8Hz), 7.25 (2H, d, J = 9Hz), 7.14(1H, d, J=47Hz), 6.87(2H, d, J=9Hz), 4.82(1H, t, J=4Hz), 4.81(lH, d, J=11Hz), 4.70-4.60 (1H, m), 4.43-4.33(1H, m), 4.38(1H, d, J=11Hz), 3.95(2H, s), 3.79(3H, s), 3.76(2H, d, J=12Hz) , 3.65(2H, d, J=12Hz), 3.23-3.08(1H, m), 2.91-2.61(4H, m), 2.32-1.50(14H, m), 1.45(3H, s), 1.40(3H, s), 1.19(3H, s), 1.03(3H, s), 0.93(3H, s), 0.70-0.60(1H, m).

Mass Spectrum (EI, m/z): 910[M ⁺ ].

(Reference Example 35)

2-Chloro-5-[3-(methoxycarbonyl)phenyl]pyrimidine

To a solution of 1.93 g (10.0 mmol) of 2-chloro-5-bromopyrimidine in 30 ml of toluene was added 4.12 g (30.0 mmol) of potassium carbonate, 1.89 g (10.5 mmol) of 3-(methoxycarbonyl)phenylboronic acid and 1.0 g (0.87 mmol) of tetrakis(triphenylphosphine)palladium(0), and the reaction solution was stirred at 110°C for 10.5 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=95/5-0/100 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 0.37 g of The title compound as a yellow solid (Yield: 14%).

¹ H-NMR spectrum (300MHz, CDCl ₃ ) δppm: 8.87 (2H, s), 8.25 (1H, t, J=2Hz), 8.16 (1H, dt, J=8, 2Hz), 7.75 (1H, ddd, J=8, 2, 1Hz), 7.62(1H, t, J=8Hz), 3.98(3H, s).

Mass Spectrum (CI, m/z): 249[(M+1) ⁺ ].

(Reference Example 36)

2-Chloro-5-methylthiopyrimidine

A solution of 1.00 g (5.17 mmol) of 5-bromo-2-chloropyrimidine and 551 μl (6.20 mmol) of dimethyl disulfide in 26 ml of tetrahydrofuran was cooled to -78°C, and 1.89 ml (5.17 mmol) of 2.73N n-Butyllithium/n-hexane solution, and the reaction solution was stirred for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution was added to the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=90/10 (V/V)] and the fraction containing the desired compound was concentrated under reduced pressure to obtain 149 mg of the title compound as a white solid (Yield: 18%).

¹ H-NMR spectrum (500MHz, CDCl ₃ ) δppm: 8.49 (2H, s), 2.54 (3H, s).

(Reference Example 37)

(5S)-4-(4,4-difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-((R )-2-hydroxy-2-phenylacetyl)piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7 , 8-Tetrahydroquinoline

(37-1) Preparation of the title compound

To 501 mg (0.742 mmol) of (-)-4-(4,4-difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl) Phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8- To the tetrahydroquinoline was added 113 mg (0.743 mmol) (R)-D-(-)-mandelic acid, 255 μl (1.46 mmol) diisopropylethylamine and 5 ml dichloromethane. Then, 143 mg (0.746 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added to the reaction solution, and the reaction solution was stirred at room temperature for 20 hours. Further, 143 mg (0.746 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 133 mg (1.09 mmol) of 4-dimethylaminopyridine were added to the reaction solution, The reaction solution was stirred at room temperature for 4 days. Water was added to the reaction solution, and the reaction solution was extracted three times with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=80/20 (V/V)] to obtain 156 mg of the title compound as a white solid (yield: 26%).

¹ H-NMR spectrum (300MHz, CD ₂ Cl ₂ ) δppm: 7.61, 7.54 (total 2H, each d, J=8Hz), 7.42-6.98 (10H, m), 6.85 (2H, d, J=8Hz), 5.11 (1H, d, J = 6Hz), 4.88-4.28 (2H, m), 4.80, 4.78 (total 1H, each d, J = 10, 11Hz), 4.71, 4.66 (total 1H, each d, J = 6 , 7Hz), 4.38, 4.37 (total 1H, each d, J=11Hz), 3.76 (3H, s), 3.63-3.53, 3.45-3.34 (total 1H, each m), 3.24-3.05 (1H, m), 2.91-2.39 (4H, m), 2.29-2.06 (3H, m), 2.01-1.43 (11H, m), 1.19 (3H, s), 1.06, 1.05 (total 3H, each s), 0.76-0.58 (1H , m).

Mass Spectrum (APCI POSITIVE, m/z): 809[(M+1) ⁺ ].

(37-2) Determination of the absolute configuration of the title compound

800 µl of methanol was added to 3.5 mg of the title compound obtained in Reference Example (37-1) to be dissolved, and then methanol was evaporated slowly and naturally to obtain a needle-shaped single crystal. The obtained single crystal was subjected to X-ray crystal structure analysis.

β＝90.3970(19)°，

Z＝2和D_calc＝1.293g/cm³。得到24045反射的最终R值0.0599。Diffraction intensity data were collected under an extremely low temperature (-150°C) airflow using the Rigaku R-AXIS RAPID, a device for analyzing X-ray structures of single crystals. After the structure was determined by the direct method of the software CrystalStructure, the structure was refined by the full matrix least squares method, in which the temperature coefficient of non-hydrogen atoms is anisotropic and that of hydrogen atoms is isotropic. The obtained crystallographic data is C ₄₆ H ₅₀ F ₆ N ₂ O ₄ , M _w =808.90, monoclinic crystal system, space group P2 ₁ ,

β=90.3970(19)°,

Z = 2 and D _calc = 1.293 g/cm ³ . A final R-value of 0.0599 was obtained for 24045 reflections.

The absolute configuration of the other asymmetric carbon of the title compound was determined from the fact that the absolute configuration of the asymmetric carbon of the mandelic acid moiety introduced into the compound was the R configuration. The absolute configuration of the carbon at the 5-position of 5,6,7,8-tetrahydroquinoline is S configuration, and the 1-position of fluoro[4-(trifluoromethyl)phenyl]methyl The absolute configuration of the carbon is the S configuration, and the chemical structure including the absolute configuration of the title compound is shown above.

Compound names and chemical structural formulas including absolute configurations of the respective compounds of Examples and Reference Examples are shown in Table 1 below (Tables 1-1 to 1-18). The absolute configurations in the following chemical structural formulas are the same as those represented in the above general formula (I-1).

[Table 1]

[Table 1-1]

[Table 1-2]

[Table 1-3]

[Table 1-4]

[Table 1-5]

[Table 1-6]

[Table 1-7]

[Table 1-8]

[Table 1-9]

[Table 1-10]

[Table 1-11]

[Table 1-12]

[Table 1-13]

[Table 1-14]

[Table 1-15]

[Table 1-16]

[Table 1-17]

[Table 1-18]

(Test Example 1) CETP inhibitory activity test (in vitro, buffer-based)

(1) Preparation of recombinant HDL

Cholesterol (1.125 μmol), phosphatidylcholine (4.5 μmol) and [ ¹⁴ C]-labeled cholesteryl ester (2.0 μCi; 40 μl) were placed in a glass test tube and mixed thoroughly by vortexing, and dried under nitrogen flow to form film. The resulting mixture was dissolved in ethanol (200 μl), which was referred to as solution A. Put PBS solution [mixed solution of Na ₂ HPO ₄ (30 mM), KH ₂ PO ₄ (8.8 mM), NaCl (60 mM) and EDTA (pH 7.4; 0.67 mM); 4 ml] in the tube, and vortex under nitrogen flow The reaction solution was vigorously stirred. The above solution A was gradually injected into the mixture with a syringe, and the reaction solution was vigorously stirred by vortexing under nitrogen flow for 5 minutes. Sodium cholate (200 mM; 0.38 ml) was added to the resulting mixture and the reaction solution was stirred for 2 minutes. ApoA-I protein (3 mg) was added to the resulting mixture and the reaction solution was stirred for 2 minutes. The resulting mixture was adjusted to 5 ml with PBS solution, and then dialyzed against PBS solution. The resulting mixture is called recombinant HDL.

(2) Preparation of receptor lipoprotein

NaBr was added to the plasma of a healthy person, the density of the mixture was adjusted to 1.019, the mixture was subjected to density gradient centrifugation (40000 rpm, 16 hours), and the part with a density lower than 1.019 was removed. NaBr was added to the resulting mixture, the density of the solution was adjusted to 1.063, and the solution was subjected to density gradient centrifugation (40,000 rpm, 18 hours) to obtain a fraction consisting of IDL (medium density lipoprotein) and LDL (1.019<density<1.063) . The resulting fraction was dialyzed against PBS solution. The resulting mixture is called receptor lipoprotein.

(3) Determination of CETP inhibitory activity

Recombinant human CETP protein (manufactured by Roar Biomedical Company; 4.5 ng), the receptor lipoprotein (32.5 μg) described in (2) above, and 5,5′-dithio-bis-(2-nitrobenzoic acid ) (7 mM, 15 μl) was placed in a 96-well plate, and the total amount of the mixture was adjusted to 48.5 μl with PBS solution. Add the test compound [DMSO solution (concentration: 0.15, 0.5, 1.5, 5, 15, 50, 150 and 500 μM; 1.5 μl] to each well, and incubate the mixture in a constant temperature bath at 37° C. for 60 minutes. The above (1) The described recombinant HDL (50 μ l) was added to each well, and the mixture was reacted for 60 minutes in a 37° C. The mixed solution [1/1 (v/v)]; 15 μl] was added to each well, and then the mixture was placed on ice for 15 minutes. The reaction solution (80 μl) in each well was transferred to a filter plate and centrifuged at 1500 rpm for 1 minute , The filtrate passing through the filter is called the HDL fraction, and its radioactivity is measured with a scintillation counter. Compared with the situation without the test compound, the percentage of radioactive decrease in the case of adding the test compound is called the CETP inhibition percentage. Calculated from the CETP inhibition percentage _IC50 values.

(4) Results

Table 1 shows the test results of the compounds of the present invention.

[Table 2]

The compound of the present invention has excellent CETP inhibitory activity in this test and is used for treating or preventing dyslipidemia, hypercholesterolemia, low HDL cholesterolemia, high HDL cholesterolemia, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, etc. Drug.

(Test Example 2) Test of CETP inhibitory activity (in vitro, plasma-based)

(1) Preparation of donor lipoprotein

NaBr was added to human plasma, the density of the mixture was adjusted to 1.125, and the mixture was subjected to density gradient centrifugation (40000 rpm, 40 hours) to remove the part with density less than 1.125. NaBr was added to the resulting mixture, the density of the mixture was adjusted to 1.21, and the mixture was subjected to density gradient centrifugation (40000 rpm, 40 hours) to obtain a fraction with the following density: 1.125<density<1.21. The resulting fraction was dialyzed against PBS solution. The resulting mixture is referred to as the HDL ₃ fraction. Phosphatidylcholine (5 mg) and [ ³ H]-labeled cholesteryl ester (0.5 mCi; 0.5 ml) were placed in glass test tubes and dried under nitrogen flow. A PBS solution (500 µl) was added to the resulting mixture and the mixture was mixed for 30 minutes under ultrasonic irradiation. HDL ₃ fraction (1.75 mg) and lipoprotein-depleted human serum (LPDS; 12 mg) were added to the resulting mixture, and the total amount of the mixture was adjusted to 3.5 ml with a PBS solution. The resulting mixture was incubated at 37°C for 48 hours. NaBr was added to the resulting mixture, the density of the mixture was adjusted to 1.063, and the mixture was subjected to density gradient centrifugation (40000 rpm, 18 hours) to remove a portion with a density lower than 1.063. NaBr was added to the resulting fraction, the density of the mixture was adjusted to 1.21, and the mixture was subjected to density gradient centrifugation (40000 rpm, 40 hours) to obtain a fraction with the following density: 1.063<density<1.21. The resulting fraction was dialyzed against a PBS solution, and the mixture was referred to as donor lipoprotein.

(2) Determination of CETP inhibitory activity

The donor lipoprotein (2 μL) described in (1) above and the test compound [DMSO solution (concentration: 0.15, 0.5, 1.5, 5, 15, 50, 150, and 500 μM; 1 μL]) were mixed with human plasma or collected from introduced human Plasma (37 μL) of double transgenic mice of Apo B and human CETP genes (hereinafter, CETP/apoB Tg mice; J.LipidRes., 1995, volume 36, pages 1082-1091) were mixed. The mixture was added to 96- Well V-bottom plate (total 40μL). Gently mix the mixture and then react at 37°C for 2 hours. Move the 96-well V-bottom plate to ice, and add a precipitant [mixed solution of magnesium chloride (200mM) and 0.2% dextran sulfate [1/1 (v/v)]; 10 μ l] was added to each well, and then the mixture was placed on ice for 15 minutes. The reaction solution (40 μ l) in each well was moved to a filter plate and centrifuged at 1500 rpm for 1 minute. The filtrate passing through the filter is called the HDL part, and the part remaining on the filter is called the LDL part, and the radioactivity of each part is measured with a scintillation counter. According to the following formula, the HDL before and after the reaction at 37 ° C The percent cholesteryl ester transfer was calculated from the radioactivity of the fraction and the LDL fraction.

Transfer percentage of cholesteryl ester (%)

=[[Radioactivity of LDL fraction (after reaction)−Radioactivity of LDL fraction (before reaction)]/[Radioactivity of LDL fraction (after reaction)+Radioactivity of HDL fraction (after reaction)]]×100

The percentage decrease in the percentage transfer of cholesteryl ester with the addition of the test compound compared to the case without the addition of the test compound is referred to as the percentage CETP inhibition. _IC50 values were calculated from percent inhibition of CETP.

The compound of the present invention has excellent CETP inhibitory activity in this test and is used for treating or preventing dyslipidemia, hypercholesterolemia, low HDL cholesterolemia, high HDL cholesterolemia, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, etc. Drug.

(Test Example 3) Test of CETP inhibitory activity (in vitro, fluorescence, plasma-based)

Reagent A (73 μl) manufactured by Roar Biomedical Co., Ltd. of the ex vivo CETP activity assay (RB-EVAK) was mixed with reagent B (311 μl) from the same source to prepare reagent C. 2.5 μl of Reagent C was mixed with human plasma or plasma collected from CETP/ApoB Tg mice (46.5 μl), and the mixture was added to a 96-well black plate (Cat. 3694 manufactured by Half Area, Corning). The test compound [DMSO solution (concentration: 0.15, 0.5, 1.5, 5, 15, 50, 150 and 500 μM; 1 μl] was added to each well, and the mixture was mixed gently. The mixture was reacted in a constant temperature bath at 37° C. for 90 minutes, and the Fluorescent plate reader (manufactured by LJL Biosystems; Analyst HT) measures the fluorescence intensity (excitation wavelength: 485nm; fluorescence wavelength: 530nm) of the sample in each well. The fluorescence intensity in the reaction using the blood plasma of wild-type mice is used as The blank was subtracted, and compared with the situation without the test compound, the percentage decrease of the fluorescence intensity in the case of adding the test compound was called the CETP inhibition percentage. The IC ₅₀ value was calculated from the CETP inhibition percentage.

The compound of the present invention has excellent CETP inhibitory activity in this test and is used for treating or preventing dyslipidemia, hypercholesterolemia, low HDL cholesterolemia, high HDL cholesterolemia, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, etc. Drug.

(Test Example 4) Test of pharmacological action on mice (in vivo and in vitro) (1) Administration of compound

The test compound was dissolved in a mixed solvent of propylene glycol-Tween80 (trade name) [4/1 (v/v)] and orally administered to CETP/apoB Tg mice for 2 or 7 days. Blood samples were collected before dosing and 14 or 24 hours after dosing on the second or seventh day.

(2) Determination of cholesterol content in plasma

The cholesterol content in plasma was measured using a commercially available measurement kit (Cholesterol-E Wako, manufactured by Wako Junyaku Co., Ltd.).

(3) Determination of HDL cholesterol and non-HDL cholesterol content

Lipoprotein status was analyzed by HPLC (column: Lipopropack XL, manufactured by Tosoh Co.). The content of HDL cholesterol and non-HDL cholesterol was calculated according to the following calculation formula.

HDL cholesterol content = cholesterol content in plasma × (peak area of HDL cholesterol/sum of each peak area)

Non-HDL cholesterol content = cholesterol content in plasma × (non-HDL cholesterol peak area/sum of each peak area)

(4) Preparation of donor lipoprotein

NaBr was added to human plasma, the density of the mixture was adjusted to 1.125, and the mixture was subjected to density gradient centrifugation (40000 rpm, 40 hours) to remove the portion with a density lower than 1.125. NaBr was added to the resulting mixture, the density of the mixture was adjusted to 1.21, and the mixture was subjected to density gradient centrifugation (40000 rpm, 40 hours) to obtain a fraction with the following density: 1.125<density<1.21. The obtained fraction was dialyzed against PBS solution, and the resulting mixture was referred to as HDL ₃ fraction. Phosphatidylcholine (5 mg) and tritiated cholesteryl ester (0.5 mCi; 0.5 ml) were placed in glass test tubes and dried under nitrogen flow. A PBS solution (500 µl) was added to the resulting mixture, and the mixture was mixed for 30 minutes under ultrasonic irradiation. HDL3 fraction (1.75 mg) and lipoprotein-depleted human serum (12 mg) were added to the resulting mixture, and the total amount of the mixture was adjusted to 3.5 ml with PBS solution. The resulting mixture was incubated at 37°C for 48 hours. NaBr was added to the resulting mixture, the density of the mixture was adjusted to 1.063, and the mixture was subjected to density gradient centrifugation (40000 rpm, 18 hours) to remove a portion with a density lower than 1.063. NaBr was added to the obtained fraction, the density of the mixture was adjusted to 1.21, and the mixture was subjected to density gradient centrifugation (40000 rpm, 40 hours) to obtain a fraction with the following density: 1.063<density<1.21. The resulting fraction was dialyzed against a PBS solution, and the resulting mixture was referred to as donor lipoprotein.

(5) Determination of CETP inhibitory activity (fluorescence, in vitro)

Reagent C was prepared by mixing Reagent A (73 µl) and Reagent B (311 µl) of Roar Biomedical's Ex Vitro CETP Activity Assay (RB-EVAK). 1 µl of Reagent C and plasma (19 µl) from the test animal were added to a black 384-well round bottom plate (Corning No. 3676). The mixture was allowed to react in a thermostat at 37°C for 90 minutes, and the fluorescence intensity (excitation wavelength: 485 nm, fluorescence wavelength: 530 nm) of the samples in each well was measured with a fluorescence plate reader (manufactured by LJLBiosystems: Analyst HT). The fluorescence intensity in the reaction using the plasma of the wild-type mouse was subtracted as a blank, and the percentage decrease of the fluorescence intensity in the case of adding the test compound compared to the case of not adding the test compound was called the CETP inhibition percentage.

In this test, the compound of the present invention has excellent CETP inhibitory activity, the effect of increasing the concentration of HDL cholesterol or the effect of reducing the concentration of LDL cholesterol, and is used for the treatment or prevention of dyslipidemia, hypercholesterolemia, low HDL cholesterol, and high HDL cholesterol. Syndrome, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, etc.

(Preparation Example 1) Hard Capsules

Hard capsules were prepared by filling the powdered compound of Example 1 (100 mg), lactose (150 mg), cellulose (50 mg) and magnesium stearate (6 mg) into standard two-part hard gelatin capsules, which were washed , then dry.

(Preparation Example 2) Soft Capsules

A mixture of readily absorbable oil materials such as soybean oil and olive oil and the compound of Example 2 was injected into gelatin so as to contain 100 mg of the active ingredient to prepare soft capsules, which were washed and then dried.

(Preparation Example 3) tablet

According to methods well known in the field of formulation science, the compound of Example 3 (100 mg), colloidal silicon dioxide (0.2 mg), magnesium stearate (0.2 mg), microcrystalline cellulose (0.2 mg), starch (0.2 mg) were used and lactose (98.8 mg) to prepare tablets. The resulting tablets may be coated, if desired.

Industrial Applicability

In terms of CETP inhibitory activity, increasing the effect on HDL cholesterol concentration, reducing the effect on LDL cholesterol concentration, rapidly exerting pharmacological effects, prolonging pharmacological effects, physical stability, solubility, oral absorption, blood drug concentration, cell membrane permeability , metabolic stability, tissue migration, bioavailability (BA), drug-drug interaction, toxicity, etc., the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has excellent properties and can be used as medicine for warm-blooded animals (especially humans). Above-mentioned medicine is treatment or prevention, preferably dyslipidemia, hypercholesterolemia, low HDL cholesterolemia, high HDL cholesterolemia, hypertriglyceridemia, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease (comprising heart failure , myocardial infarction, angina pectoris, myocardial ischemia, cardiovascular disorders and restenosis associated with angioplasty), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (including diabetic vascular complications) or obesity, More preferably, dyslipidemia, hypercholesterolemia, low HDL cholesterolemia, high HDL cholesterolemia, arteriosclerosis, arteriosclerotic heart disease, or coronary heart disease, more preferably dyslipidemia, low HDL cholesterolemia, arteriosclerosis, or coronary heart disease And even more preferably a drug for low HDL cholesterol or arteriosclerosis.

Claims (41)

1. compound or its pharmacy acceptable salt by general formula (I) expression:

R wherein ¹Expression hydrogen atom, C ₁-C ₆Alkyl, hydroxyl (C ₁-C ₆Alkyl) group, (C ₁-C ₆Alkoxyl group)-(C ₁-C ₆Alkyl) group, hydroxyl (C ₁-C ₆Alkoxyl group)-(C ₁-C ₆Alkyl) group, (C ₁-C ₆Alkyl) amino-(C ₁-C ₆Alkyl) group, hydroxyl (C ₁-C ₆Alkyl) amino-(C ₁-C ₆Alkyl) group, [N-(C ₁-C ₆Alkyl)-N-hydroxyl (C ₁-C ₆Alkyl) amino]-(C ₁-C ₆Alkyl) group, (C ₁-C ₆Alkyl) sulfuryl amino-(C ₁-C ₆Alkyl) group, [N-(C ₁-C ₆Alkyl)-N-(C ₁-C ₆Alkyl) sulfuryl amino]-(C ₁-C ₆Alkyl) group, carboxyl (C ₁-C ₆Alkyl) group, halo (C ₁-C ₆Alkyl) group, (C ₃-C ₈Cycloalkyl)-(C ₁-C ₆Alkyl) group, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₃-C ₈Cycloalkyl, C ₃-C ₈Cycloalkenyl group, hydroxyl, C ₁-C ₆Alkoxyl group, hydroxyl (C ₁-C ₆Alkoxyl group) group, (C ₁-C ₆Alkoxyl group)-(C ₁-C ₆Alkoxyl group) group, (C ₁-C ₆Alkyl) alkylsulfonyl-(C ₁-C ₆Alkoxyl group) group, carboxyl (C ₁-C ₆Alkoxyl group) group, halo (C ₁-C ₆Alkoxyl group) group, C ₁-C ₆Alkyl sulfenyl, C ₁-C ₆Alkyl sulfinyl, C ₁-C ₆Alkyl sulphonyl, amino, C ₁-C ₆Alkylamino, two (C ₁-C ₆Alkyl) amino, hydroxyl (C ₁-C ₆Alkyl) amino, N-(C ₁-C ₆Alkyl)-N-hydroxyl (C ₁-C ₆Alkyl) amino, the amino, (C of formyl radical ₁-C ₆Alkyl) carbonylamino, carboxyl, (C ₁-C ₆Alkoxyl group) carbonyl, formamyl, (C ₁-C ₆Alkylamino) carbonyl, two (C ₁-C ₆Alkyl) aminocarboxyl, cyano group, halogeno-group, phenyl, wherein substituting group represents to be independently selected from the phenyl of replacement of 1-4 the group of substituting group group α, 5 yuan or 6 yuan of aromatic heterocyclic groups, wherein substituting group represents to be independently selected from 5 yuan or 6 yuan of aromatic heterocyclic groups of replacement of 1-4 the group of substituting group group α, 5 yuan or 6 yuan of saturated heterocyclic groups, wherein substituting group represents to be independently selected from 5 yuan or 6 yuan of saturated heterocyclic groups of replacement of 1-4 the group of substituting group group α, 5 yuan or 6 yuan of saturated heterocyclic-(C ₁-C ₆Alkyl) group, wherein substituting group represents to be independently selected from 5 yuan or 6 yuan of saturated heterocyclic-(C of replacement of 1-4 the group of substituting group group α ₁-C ₆Alkyl) group, 5 yuan or 6 yuan of saturated heterocyclyl oxygen bases, wherein substituting group represent to be independently selected from 5 yuan of replacement of 1-4 group of substituting group group α or 6 yuan of saturated heterocyclyl oxygen bases, 5 yuan or 6 yuan of saturated heterocyclic carbonyls or wherein substituting group represent to be independently selected from 5 yuan of replacement of 1-4 group of substituting group group α or 6 yuan of saturated heterocyclic carbonyls and

Substituting group group α represents C ₁-C ₆Alkyl, hydroxyl (C ₁-C ₆Alkyl) group, halo (C ₁-C ₆Alkyl) group, (C ₃-C ₈Cycloalkyl)-(C ₁-C ₆Alkyl) group, C ₃-C ₈Cycloalkyl, hydroxyl, C ₁-C ₆Alkoxyl group, halo (C ₁-C ₆Alkoxyl group) group, C ₁-C ₆Alkylamino, two (C ₁-C ₆Alkyl) amino, carboxyl, (C ₁-C ₆Alkoxyl group) carbonyl, formamyl, (C ₁-C ₆Alkylamino) carbonyl, two (C ₁-C ₆Alkyl) aminocarboxyl, cyano group, halogeno-group and oxo base.

2. according to compound or its pharmacy acceptable salt of the general formula (I-1) of claim 1 expression:

。

3. according to compound or its pharmacy acceptable salt, the wherein R of claim 2 ¹Be hydrogen atom, C ₁-C ₆Alkyl, hydroxyl (C ₁-C ₆Alkyl) group, (C ₁-C ₆Alkoxyl group)-(C ₁-C ₆Alkyl) group, (C ₁-C ₆Alkyl) amino-(C ₁-C ₆Alkyl) group, [N-(C ₁-C ₆Alkyl)-N-hydroxyl (C ₁-C ₆Alkyl) amino]-(C ₁-C ₆Alkyl) group, [N-(C ₁-C ₆Alkyl)-N-(C ₁-C ₆Alkyl) sulfuryl amino]-(C ₁-C ₆Alkyl) group, carboxyl (C ₁-C ₆Alkyl) group, halo (C ₁-C ₆Alkyl) group, C ₂-C ₆Alkenyl, C ₃-C ₈Cycloalkyl, C ₃-C ₈Cycloalkenyl group, hydroxyl, C ₁-C ₆Alkoxyl group, hydroxyl (C ₁-C ₆Alkoxyl group) group, (C ₁-C ₆Alkyl) alkylsulfonyl-(C ₁-C ₆Alkoxyl group) group, carboxyl (C ₁-C ₆Alkoxyl group) group, halo (C ₁-C ₆Alkoxyl group) group, C ₁-C ₆Alkyl sulfenyl, C ₁-C ₆Alkyl sulphonyl, N-(C ₁-C ₆Alkyl)-N-hydroxyl (C ₁-C ₆Alkyl) amino, (C ₁-C ₆Alkylamino) carbonyl, two (C ₁-C ₆Alkyl) aminocarboxyl, cyano group or halogeno-group.

4. according to compound or its pharmacy acceptable salt, the wherein R of claim 2 ¹Be hydrogen atom, C ₁-C ₄Alkyl, hydroxyl (C ₁-C ₄Alkyl) group, (C ₁-C ₄Alkoxyl group)-(C ₁-C ₄Alkyl) group, halo (C ₁-C ₄Alkyl) group, C ₁-C ₄Alkoxyl group, hydroxyl (C ₁-C ₆Alkoxyl group) group or (C ₁-C ₄Alkyl) alkylsulfonyl-(C ₁-C ₄Alkoxyl group) group.

5. according to compound or its pharmacy acceptable salt, the wherein R of claim 2 ¹Be C ₁-C ₄Alkyl, halo (C ₁-C ₄Alkyl) group, C ₁-C ₄Alkoxyl group or hydroxyl (C ₁-C ₆Alkoxyl group) group.

6. according to compound or its pharmacy acceptable salt, the wherein R of claim 2 ¹Be C ₁-C ₄Alkyl.

7. according to compound or its pharmacy acceptable salt, the wherein R of claim 2 ¹Be halo (C ₁-C ₄Alkyl) group.

8. according to compound or its pharmacy acceptable salt, the wherein R of claim 2 ¹Be C ₁-C ₄Alkoxyl group.

9. according to compound or its pharmacy acceptable salt, the wherein R of claim 2 ¹Be hydroxyl (C ₁-C ₆Alkoxyl group) group.

10. according to compound or its pharmacy acceptable salt, the wherein R of claim 2 ¹Be (C ₁-C ₄Alkyl) alkylsulfonyl-(C ₁-C ₄Alkoxyl group) group.

11. according to compound or its pharmacy acceptable salt of claim 2, wherein

R ¹Be wherein substituting group represent to be independently selected from substituting group group α 1 1-4 group replacement phenyl, wherein substituting group represent to be independently selected from 5 yuan of replacement of 1-4 group of substituting group group α 1 or 6 yuan of aromatic heterocyclic groups, 5 yuan or 6 yuan of saturated heterocyclic groups, wherein substituting group represent to be independently selected from 5 yuan of replacement of 1-4 group of substituting group group α 1 or 6 yuan of saturated heterocyclic groups, wherein substituting group represent to be independently selected from 5 yuan of replacement of 1-4 group of substituting group group α 1 or 6 yuan of saturated heterocyclyl oxygen bases or 5 yuan or 6 yuan of saturated heterocyclyl carbonyls and

Substituting group group α 1 expression C ₁-C ₆Alkyl, hydroxyl, carboxyl and oxo base.

12. according to compound or its pharmacy acceptable salt of claim 2, wherein

R ¹Be 5 yuan or 6 yuan of nitrogenous saturated heterocyclic groups, wherein substituting group represent to be independently selected from 5 yuan of replacement of 1-4 group of substituting group group α 2 or 6 yuan of nitrogenous saturated heterocyclic groups, wherein substituting group represent to be independently selected from 5 yuan of replacement of 1-4 group of substituting group group α 2 or 6 yuan of nitrogenous saturated heterocyclyl oxygen bases or 5 yuan or 6 yuan of nitrogenous saturated heterocyclyl carbonyls and

Substituting group group α 2 expression C ₁-C ₄Alkyl and hydroxyl.

13. according to compound or its pharmacy acceptable salt of claim 2, wherein

R ¹Be pyrrolidyl, the piperazinyl of replacement, the pyrrolidyl oxygen base of replacement or the piperidyl oxygen base of replacement that replaces, wherein the substituting group of pyrrolidyl, piperazinyl, pyrrolidyl oxygen base and piperidyl oxygen base represent to be independently selected from substituting group group α 3 or morpholinyl carbonyl 1-2 group and

Substituting group group α 3 expression methyl and hydroxyls.

14. compound or its pharmacy acceptable salt, wherein R according to claim 2 ¹Be the phenyl that replaces, substituting group wherein represents to be independently selected from 1-2 the group of substituting group group α 1.

15. according to compound or its pharmacy acceptable salt of claim 2, it is selected from

(5S)-and 4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-7,7-dimethyl-2-{1-[5-(4-methylpiperazine-1-yl) pyrimidine-2-base] piperidin-4-yl }-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-2-{1-[5-(2-hydroxyl-oxethyl) pyrimidine-2-base] piperidin-4-yl }-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-and 2-{1-[5-(4-carboxyl butoxy) pyrimidine-2-base] piperidin-4-yl }-4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-and 2-{1-[5-(4-carboxybutyl) pyrimidine-2-base] piperidin-4-yl }-4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-and 4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-7,7-dimethyl-2-{1-[5-(methylamino formyl radical) pyrimidine-2-base] piperidin-4-yl }-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-and 4-(4,4-difluoro cyclohexyl)-2-{1-[5-(formyl-dimethylamino) pyrimidine-2-base] piperidin-4-yl }-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-and 4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-7,7-dimethyl-2-{1-[5-(morpholine-4-base carbonyl) pyrimidine-2-base] piperidin-4-yl }-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-2-{1-(5-{[(2-hydroxyethyl) (methyl) amino] methyl } pyrimidine-2-base) piperidin-4-yl }-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-2-[1-(5-{[(2S)-2-hydroxypropyl] the oxygen base } pyrimidine-2-base) piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-and 4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-7,7-dimethyl-2-(1-{5-[(1-methyl piperidine-4-yl) oxygen base] pyrimidine-2-base } piperidin-4-yl)-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-and 4-(4,4-difluoro cyclohexyl)-2-[1-(5-{[(2S)-2, the 3-dihydroxypropyl] the oxygen base } pyrimidine-2-base) piperidin-4-yl]-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-and 4-(4,4-difluoro cyclohexyl)-2-[1-(5-{[(2R)-2, the 3-dihydroxypropyl] the oxygen base } pyrimidine-2-base) piperidin-4-yl]-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-and 4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-7,7-dimethyl-2-[1-(5-{[(3R)-1-methylpyrrolidin-3-yl] the oxygen base } pyrimidine-2-base) piperidin-4-yl]-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-2-[1-(5-{[(2R)-2-hydroxypropyl] the oxygen base } pyrimidine-2-base) piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-2-{1-[5-(3-hydroxy-3-methyl butoxy) pyrimidine-2-base] piperidin-4-yl }-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-2-{1-[5-(2-hydroxy-2-methyl propoxy-) pyrimidine-2-base] piperidin-4-yl }-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-and 4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-7,7-dimethyl-2-(1-{5-[3-(methylsulfonyl) propoxy-] pyrimidine-2-base } piperidin-4-yl)-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-2-{1-[5-(3-hydroxyl propoxy-) pyrimidine-2-base] piperidin-4-yl }-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-and 4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-7,7-dimethyl-2-{1-[5-(3,3,3-trifluoro propoxy-) pyrimidine-2-base] piperidin-4-yl }-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-2-(1-{5-[3-hydroxyl-2-(methylol) propoxy-] pyrimidine-2-base } piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-2-(1-{5-[3-hydroxyl-2-(methylol)-2-methyl propoxy-] pyrimidine-2-base } piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-and 4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-7,7-dimethyl-2-[1-(5-{[methyl (methylsulfonyl) amino] methyl } pyrimidine-2-base) piperidin-4-yl]-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-and 4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-7,7-dimethyl-2-[1-(5-{[methyl (third-2-base alkylsulfonyl) amino] methyl } pyrimidine-2-base) piperidin-4-yl]-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-and 4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-7,7-dimethyl-2-[1-(5-methylthiopyrimidine-2-yl) piperidin-4-yl]-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-and 4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-7,7-dimethyl-2-{1-[5-(methylsulfonyl) pyrimidine-2-base] piperidin-4-yl }-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-and 2-{1-[5-(3-carboxyl phenyl) pyrimidine-2-base] piperidin-4-yl }-4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5-alcohol,

(5S)-4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl-2-(1-{5-[(2-hydroxyethyl) (methyl) amino] pyrimidine-2-base piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5-alcohol and

(5S)-4-(4,4-difluoro cyclohexyl)-3-{ (S)-fluoro [4-(trifluoromethyl) phenyl] methyl }-2-(1-{5-[(3S)-3-hydroxyl pyrrolidine-1-yl] pyrimidine-2-base } piperidin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-5-alcohol.

16. a medicinal compositions, its contain as activeconstituents according to each compound or its pharmacy acceptable salt among the claim 1-15.

17. according to the medicinal compositions of claim 16, it is used for the treatment of or prevents hyperlipemia, hypercholesterolemia, low HDL hypercholesterolemia, high LDL hypercholesterolemia, hypertriglyceridemia, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, cerebro-vascular diseases, surrounding blood vessel disease or obesity.

18. according to the medicinal compositions of claim 16, it is used for the treatment of or prevents hyperlipemia, low HDL hypercholesterolemia, arteriosclerosis or coronary heart disease.

19. according to the medicinal compositions of claim 16, it is used for the treatment of or prevents the low HDL hypercholesterolemia.

20. according to the medicinal compositions of claim 16, it is used for the treatment of or the prevention of arterial sclerosis.

21. according to the medicinal compositions of claim 16, the disease that it is used for the treatment of or prevents the decline because of HDL cholesterol concentration in the blood to cause.

22. according to the medicinal compositions of claim 16, the disease that it is used for the treatment of or prevents the rising because of LDL cholesterol concentration in the blood to cause.

23. a medicine that suppresses CETP, its comprise as activeconstituents according to each compound or its pharmacy acceptable salt among the claim 1-15.

24. a medicine that improves the HDL cholesterol concentration, its comprise as activeconstituents according to each compound or its pharmacy acceptable salt among the claim 1-15.

25. a medicine that reduces the LDL cholesterol concentration, its comprise as activeconstituents according to each compound or its pharmacy acceptable salt among the claim 1-15.

26. according among the claim 1-15 each compound or its pharmacy acceptable salt in the purposes of preparation in the medicinal compositions.

27. according to the purposes of the preparation medicinal compositions of claim 26, described medicinal compositions is used for the treatment of or prevents hyperlipemia, hypercholesterolemia, low HDL hypercholesterolemia, high LDL hypercholesterolemia, hypertriglyceridemia, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, cerebro-vascular diseases, surrounding blood vessel disease or obesity.

28. according to the purposes of the preparation medicinal compositions of claim 26, described medicinal compositions is used for the treatment of or prevents hyperlipemia, low HDL hypercholesterolemia, arteriosclerosis or coronary heart disease.

29. according to the purposes of the preparation medicinal compositions of claim 26, described medicinal compositions is used for the treatment of or prevents the low HDL hypercholesterolemia.

30. according to the purposes of the preparation medicinal compositions of claim 26, described medicinal compositions is used for the treatment of or the prevention of arterial sclerosis.

31. according to each compound or its pharmacy acceptable salt among the claim 1-15, it is used for the treatment of or prophylactic method.

32. according to compound or its pharmacy acceptable salt of claim 31, disease wherein is hyperlipemia, hypercholesterolemia, low HDL hypercholesterolemia, high LDL hypercholesterolemia, hypertriglyceridemia, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, cerebro-vascular diseases, surrounding blood vessel disease or obesity.

33. according to compound or its pharmacy acceptable salt of claim 31, disease wherein is hyperlipemia, low HDL hypercholesterolemia, arteriosclerosis or coronary heart disease.

34. according to compound or its pharmacy acceptable salt of claim 31, disease wherein is the low HDL hypercholesterolemia.

35. according to compound or its pharmacy acceptable salt of claim 31, disease wherein is an arteriosclerosis.

36. a treatment or prophylactic method, it comprise give warm-blooded animal pharmacology significant quantity according to each compound or its pharmacy acceptable salt among the claim 1-15.

37. according to the method for claim 36, disease wherein is hyperlipemia, hypercholesterolemia, low HDL hypercholesterolemia, high HDL hypercholesterolemia, hypertriglyceridemia, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, cerebro-vascular diseases, surrounding blood vessel disease or obesity.

38. according to the method for claim 36, disease wherein is hyperlipemia, low HDL hypercholesterolemia, arteriosclerosis or coronary heart disease.

39. according to the method for claim 36, disease wherein is the low HDL hypercholesterolemia.

40. according to the method for claim 36, disease wherein is an arteriosclerosis.

41. according to each method among the claim 36-40, warm-blooded animal wherein is the people.